II - Hallmarks of Skin Cancer

Transcrição

Application │RTG 2099/1
Cancer Cell Dissemination
Primary Resistance
Novel Targets
Heidelberg University
DKFZ Heidelberg
Designated Speaker: Prof. Dr. S. Goerdt
Designated Vice-Speaker: Prof. Dr. M. Leverkus
London Coordinator: Prof. A. Hayday, PhD
Proposed Funding Period
01/04/2015 – 30/09/2019
Table of Contents
Page
1
General Information
1
1.1
Title in English and German
1
1.2
Host University
1
1.3
Participating Researchers
1
1.4
Associated Researchers / Lecturers
2
1.5
Summary in English and German
2
1.5.1
Summary in English
2
1.5.2
Summary in German
3
1.6
Funding Period
4
1.7
Number of PhD and MD positions
4
2
Profile of the Research Training Group
4
3
Research Program
5
3.1
Overview and Aims
5
3.1.1
Research Area A – Cancer Cell Dissemination
6
3.1.2
Research Area B – Primary Resistance to
Cell Death and Immunity
6
3.1.3
Novel Targets – A Cross-sectional Approach
7
3.1.4
Collaboration, Methods, Model Systems
7
3.2
Project Descriptions
Project Package A1 Cancer Stem Cells
8
Project 1 (Sleeman)
8
Project 2 (Utikal)
10
Project 3 (I. Augustin/Boutros)
12
Project 4 (Boutros)
14
Project Package A2 Invasion and Metastasis
16
Project 5 (Angel)
16
Project 6 (Schneider/Winkler)
18
Project 7 (Géraud/Goerdt)
20
I
Page
Research Area B – Primary Resistance to
Cell Death and Immunity
Project Package B1 Primary Resistance to Cell Death
22
Project 8 (Felcht/H. Augustin)
22
Project 9 (Leverkus)
24
Project 10 (Geserick/Leverkus)
26
Project Package B2: Primary Resistance to Tumor Immunity
28
Project 11 (Lonsdorf/Enk)
28
Project 12 (Schäkel/Cerwenka)
30
Project 13 (Schmieder/Umansky)
32
4
Qualification Program
34
4.1
34
4.1.1
Seminars
35
4.1.2
Laboratory Instruction
35
4.1.3
Workshops
37
4.1.4
Student Project Development Platforms and Students’
Conferences
37
4.1.5
Transition from the First Class of Students to the Next Class
37
4.2
Guest Scientist Program
37
4.3
Additional Qualification Program – Scientific Collaboration
with the London Project Partners of the RTG
37
4.4
Only Regarding International Research Training Groups:
Research Stays at the Partner Institution
38
5
Supervision and Career Development, Equal
Opportunity / Gender Equality, Organization,
and Quality Management
39
5.1
Application and Selection Concept
39
5.2
Supervising Concept and Career Development
39
5.3
Equal Opportunity / Gender Equality in Science
40
5.4
Organization
42
5.5
Additional Aspects of Quality Management
43
II
Page
6
Scientific Environment
44
6.1
Demarcation from Existing SFBs
45
6.2
Demarcation from Preexisting Graduate Colleges
45
7
Modules / Requested Funding
45
7.1
Module Research Training Group
45
7.2
Module Substitute
47
7.3
Module Coordination
47
7.4
Module Rotational Positions
47
7.5
Module Mercator Fellows
47
7.6
Module Project-Specific Workshops
47
7.7
Module Public Relations
47
7.8
Module Start-up Grants
48
7.9
Module Equal Opportunity / Gender Equality
48
Table 1
48
Table 2
48
Table 3
48
8
Complementary Funding by the Partner Institution
49
9
Declarations
49
9.1
Relations to other SFBs
49
9.2
Collaboration with other Cooperation Partners
49
9.3
Cooperation with Corporate Partners
49
9.4
Admission of Qualification Students
49
9.5
Submissions of the Proposal to other Funding Organizations
49
9.6
Letter of Intent of the Partner Institution
49
10
Obligations
50
11
Signatures
50
III
Appendix I
1. List of Published Research Relevant to the
51
Research Program
Appendix II
1. Biographical Sketches of the Participating
70
Researchers
2. Biographical Sketches of the Associated
Researchers
Appendix III
Declarations regarding Section 9.2. “Collaboration with other
Cooperation Partners”
1. Letter of Intent by the Medical Faculty Heidelberg
regarding funding
2. Letter of Intent by the Medical Faculty Mannheim
regarding funding
3. Letter of Intent of the London Co-ordinator,
Prof. A. Hayday, King’s College and Cancer Research UK,
London, regarding Scientific Collaboration
IV
113
124
1
General information
1.1 Title in English and German
Hallmarks of Skin Cancer: Cancer Cell Dissemination, Primary Resistance, Novel Targets
Mechanismen des Hautkrebses: Metastasierung, primäre Resistenz und neue Zielstrukturen
1.2 Host University
Ruprecht-Karls-University Heidelberg and German Cancer Research Center
1.3 Participating Researchers
JECT
NAME, ACADEMIC TITLE,
DATE OF BIRTH
1
DEPARTMENT, AFFILIATION , POSTAL
ADDRESS
1
Prof. Dr. Jonathan
Sleeman, 24.02.1965
Dept. Microvascular Biology and
Pathobiology, MFM, Ludolf-KrehlStr. 13-17, 68167 Mannheim
2
Prof. Dr. Jochen Utikal,
09.11.1974
CCU Dermato-Oncology,
DKFZ/MFM, UMM, 68135
Mannheim
3
Dr. Iris Augustin,
18.03.1969
Prof. Dr. Michael
Boutros, 26.10.1970
4
Prof. Dr. Michael
Boutros, 26.10.1970
5
Prof. Dr. Peter Angel,
24.02.1959
6
7
8
9
10
11
Prof. Dr. Stefan
Schneider 10.11.1966
Prof. Dr. Frank Winkler
15.08.1971
PD Dr. Cyrill Géraud
01.06.1982
Prof. Dr. Sergij Goerdt
14.05.1959
Dr. Moritz Felcht
01.08.1979
Prof. Dr. Hellmut
Augustin 05.02.1959
Prof. Dr. Martin
Leverkus 27.12.1965
Dr. Peter Geserick
11.09.1976
Prof. Dr. Martin
Leverkus 27.12.1965
Dr. Anke Lonsdorf
08.02.1977
Prof. Dr. Alexander Enk
10.05.1963
Division of Signaling and
Functional Genomics, DKFZ, and
Dept. Cell and Molecular Biology,
MFM, INH 280, 69120 Heidelberg
Division of Signaling and
Functional Genomics, DKFZ, and
Dept. Cell and Molecular Biology,
MFM, INH 280, 69120 Heidelberg
CONTACT
(FON, FAX, EMAIL)
Fon: 0621-383-9965
Fax: 0621-383-9961
Jonathan.sleeman@med
ma.uni-heidelberg.de
DermatoOncology,
Melanoma, Stem
Cells
Fon: 06221-421955
Fax: 06221-421959
[email protected]
Signaling and
Functional
Genomics
Fon: 06221-42-1951
Fax: 06221-42-1959
[email protected]
Signaling and
Functional
Genomics
Fon: 06221-42-4570
Fax: [email protected]
Dept. Experimental Dermatology,
MFM; UMM, 68135 Mannheim
Dept. Neuro-Oncology, MFH, INH
400, 69120 Heidelberg
Fon: 0621-338-6901
Fax: 0621-383-6903
stefan.schneider@medm
a.uni-heidelberg.de
Fon: 0621-383-2280
Fax: 0621-383-3815
[email protected]
[email protected]
Fon: 0621-383-2280
Fax: 0621-383-3815
[email protected]
[email protected]
Fon: 0621-383-2344
Fax: 0621-383-4085
Martin.Leverkus@medm
a.uni-heidelberg.de
Fon: 0621-383-2344
Fax: 0621-383-4085
Peter.Geserick@medma.
uni-heidelberg.de
Fon: 06221-56-8500
Fax: 06221-56-5406
[email protected]
Fon: 06221.56-8447
Fax: 06221-56-5406
[email protected]
[email protected]
Fon: 0621-383-2048
Fax: 0621-383-3815
Astrid.schmieder@umm.
de
Dept. Dermatology, MFM;
Vascular Oncology, MFM and
DKFZ; UMM, 68135 Mannheim
Dept. Molecular Dermatology,
MFM, UMM, 68135 Mannheim
Dept. Molecular Dermatology,
MFM, UMM, 68135 Mannheim
Dept. Dermatology, MFH,
Voßstr.2, 69115 Heidelberg
12
Prof. Dr. Knut Schäkel,
18.05.1966 PD Dr.
Adelheid Cerwenka,
14.4.1968
Voßstr.2, 69115 Heidelberg
Boveri Research Group Innate
Immunity, DKFZ, INH 280, 69120
Heidelberg
13
Dr. Astrid Schmieder
05.02.1979
Prof. Dr. Viktor
Umansky 23.12.1955
Dept. Dermatology, MFM; CCU
Dermato-Oncology, DKFZ/MFM;
UMM, 68135 Mannheim
1
Vascular Biology,
Metastasis
Fon: 0621-383-4461
Fax: 0621-383-3815
[email protected]
Dept. Signal Transduction and
Growth Control, DKFZ, INH 280,
69120 Heidelberg
Dept. Dermatology, MFM, UMM,
68135 Mannheim, Germany
RESEARCH AREA
Signal
Transduction,
Tumor
Progression
Dermatology,
Vascular Biology,
Neurology, Brain
Tumors
Dermatology,
DermatoOncology,
Vascular Biology
Dermatology,
Vascular Biology
DermatoOncology;
Programmed Cell
Death
DermatoOncology;
Programmed Cell
Death
DermatoOncology;
Immunology
Dermatology,
Immunology
Dermatology
Immunology
MFM = Medical Faculty Mannheim, Heidelberg University; MFH = Medical Faculty Heidelberg, Heidelberg University;
UMM = University Medical Center Mannheim; DKFZ = German Cancer Research Center; CCU = Clinical Cooperation
Unit Dermato-Oncology Mannheim, DKFZ/MFM
1
INTRO
PRO-
The group of applicants for the Research Training Group (RTG) comprises 13 professors/lecturers
and 6 junior principal investigators. In designing the structure of the RTG, a number of factors were
taken into consideration:
1. The DFG encourages the support of scientists on their way up the academic career ladder.
Therefore, 6 projects recruited brilliant younger scientists as primary PIs who are in transition to
become independent group leaders, allowing them to take responsibility for projects in the RTG
early in their career development;
2. In addition to the 12 PhD positions we are applying for, the two Medical Faculties of Heidelberg
University and the German Cancer Research Center (DKFZ) will finance one additional PhD
position and 8 MD fellowships, amounting to a total of 21 doctoral students. To guarantee
adequate supervision of these students, 19 PIs was considered appropriate, given that each
doctoral student will be assigned two supervisors;
3. The study program we envision demands a high teaching quality and has to cover a range of
topics for which a broad basis of experts in clinical and basic science will be necessary. The
consortium of PIs we have assembled provides the requisite coverage of these topics;
4. Dermato-Oncology is a structural research focus of both Medical Faculties of Heidelberg
University and the DKFZ. The high number of participating departments in this HeidelbergMannheim Skin Cancer Alliance allows, but also dictates that a higher number of lecturers than
is recommended by the DFG for RTGs are included in this application.
1.4 Associated Researchers/Lecturers
NAME, ACADEMIC
TITLE
1
DEPARTMENT, AFFILIATION ,
POSTAL ADDRESS
INTRO
Prof. Dr. ClausDetlev Klemke
Dept. Dermatology, MFM,
UMM, 68135 Mannheim
Prof. Dr. Wiebke
Ludwig-Peitsch
Dept. Dermatology, MFM,
UMM, 68135 Mannheim
Prof. Dr. Karsten
Mahnke
69115 Heidelberg
Prof. Dr. Hugo H.
Marti
Dept.Physiology,Neurovascular Research, MFH,
69120 Heidelberg
Dr. Martin Sprick
Hi-Stem gGmbH im DKFZ,
69120 Heidelberg
CONTACT
(FON, FAX, EMAIL)
Fon: 0621-383-3918
Fax: 0621-383-3815
[email protected]
Fon: 0621-383-1054
Fax: 0621-383-3815
[email protected]
Fon: 06221-56-8170
Fax: 06221-56-1617
[email protected]
Fon:06221-54-4138
Fax:06221-54-4561
[email protected]
Fon: 06221-42-3913
Fax: 06221-42-3902
[email protected]
RESEARCH AREA
Dermatology, Skin
Surgery, cutaneous
lymphoma
Dermatology, Rare Skin
Cancers
Immunology
Vascular Physiology,
Blood Brain Barrier
Cancer stem cells,
primary culture models
of solid tumors
1.5 Summary in English and German
1.5.1 Summary in English
Skin cancer constitutes a world-wide health issue of increasing importance as its incidence is
continuously rising due to environmental factors and the aging population. Malignant melanoma is
associated with a high mortality due to its tremendous metastatic potential. A similar number of
deaths are caused annually by non-melanoma skin cancer, which is the most frequent cancer
worldwide. As considerable therapeutic optimism has been recently raised by the development of
designer drugs that target oncogenic signalling pathways and the tumor immune escape in skin
cancer, the RTG focuses on a timely and evolving field of innovative research with a major
socioeconomic impact on Western societies. The RTG will contribute considerably to a better
understanding of skin cancer biology by addressing burning questions such as the molecular and
cellular mechanisms (1) of skin cancer dissemination and metastasis, including skin cancer stem
cells and the tumor vasculature and (2) of primary skin cancer resistance to apoptosis and
immunity. All projects aim at identifying and validating novel therapeutic targets towards these
hallmarks of skin cancer. The RTG research program builds on the intense collaboration of the
applicants’ laboratories in the Heidelberg-Mannheim Skin Cancer Alliance whose collective
expertise in skin cancer biology is unique in Germany.
2
The educational program is aimed at attracting young scientists to a hitherto under-developed field
of research. The PhD/MD students will be trained in a broad portfolio of research skills and will also
receive complementary teaching to increase their clinical knowledge. The RTG will closely
collaborate with the existing Life Science Graduate Schools of Heidelberg University, and of the
German Cancer Research Center (DKFZ) to recruit the best PhD students worldwide, and to
provide teaching in basic molecular and cellular biology, as well as in general cancer biology and
oncology. The added value of the RTG teaching program will lie in applying these general topics to
the specifics of skin cancer biology and dermato-oncology. In addition, the RTG will support the
PhD/MD students to conceive and realize scientific and teaching initiatives of their own, such as
student project development platforms and student conferences. This will enable them later to
develop their own research agenda in the field.
In addition, the RTG will profit from the close scientific collaboration set up with the St. John’s
Institute of Dermatology, King’s College, London, UK, one of the most renowned academic
institutions in clinical and experimental dermatology worldwide. Beyond the St. John’s Institute, the
RTG includes the participation of an inter-institutional, University of London and Cancer Research
UK-based faculty of scientific project partners in the Metropolitan Area of London with outstanding
expertise across the spectrum of relevant basic, translational and clinical science. The London
project partners are committed to the goals of the RTG and will engage in pushing the scientific
projects forward and help the PhD students develop their scientific carreers in an international
environment.
Altogether, the RTG will perform high quality research projects and train PhD and MD students to
work closely together to fight skin cancer. The RTG will achieve its goals by combining basic
science and clinical education with a focus on targetable hallmarks of skin cancer.
Bösartige Hauttumoren stellen aufgrund von Umweltfaktoren und aufgrund der Altersentwicklung
der Bevölkerung ein zunehmendes Gesundheitsproblem dar. Das maligne Melanom ist aufgrund
seines ausgeprägten Metastasierungspotentials mit einer hohen Mortalität vergesellschaftet. Die
epithelialen Hauttumoren sind die weltweit häufigsten bösartigen Tumoren mit einer vergleichbaren
Mortalität. An den Therapieerfolgen der neuen zielgerichteten Medikamente bei bösartigen
Hauttumoren wird deutlich, dass das GRK seinen Schwerpunkt auf ein hochaktuelles Thema legt.
Das GRK wird zum besseren Verständnis der Biologie des Hautkrebses beitragen; Hauptthema
sind die molekularen und zellulären Mechanismen (1) der Tumorzelldissemination und
Metastasierung einschl. Hautkrebsstammzellen und Tumorgefäße sowie 2) der primären
Resistenz gegenüber Apoptose und Tumorimmunabwehr. Jedes Projekt arbeitet zudem an der
Identifizierung neuer therapeutischer Zielstrukturen bei diesen „Hallmarks of Skin Cancer“. Das
RTG verstärkt die Zusammenarbeit zwischen den Arbeitsgruppen der Antragsteller, deren
gemeinschaftliche Expertise zum Thema Hautkrebs in Deutschland ihres gleichen suchen dürfte.
Das Qualifizierungsprogramm des GRK soll junge Forscher für ein bisher unterentwickeltes Gebiet
begeistern. Die Graduierten werden eine breite methodische Ausbildung in der
Grundlagenforschung und einen umfassenden Überblick über die klinische Dermato-Onkologie
erhalten. Das GRK wird mit den Graduiertenschulen der Universität Heidelberg, HBIGS, und des
DKFZ, HIGS, eng zusammenarbeiten. HBIGS wird für die Lehre in Molekular- und Zellbiologie,
HIGS in Tumorbiologie und Allgemeiner Onkologie verantwortlich sein. Der Mehrwert des GRK
wird in der Anwendung dieser Grundlagen auf die Biologie des Hautkrebses und die DermatoOnkologie liegen. Das GRK wird die Studenten dabei unterstützen, in eigener Verantwortung
Forschungs- und Lehrinitiativen wie studentische Projektentwicklungsplattformen und
Fachtagungen zu realisieren. Dies soll sie befähigen, später ein eigenes Forschungsprogramm in
der Dermato-Onkologie zu entwickeln.
Darüber hinaus wird das Forschungsprogramm und die Karriereentwicklung der Studierenden
durch die Zusammenarbeit mit dem St. John’s Institute of Dermatology in London, einer der
bekanntesten Forschungseinrichtungen der Dermatologie, an Internationalität gewinnen.
Zusätzlich kann sich das GRK auf eine interinstitutionelle Gruppe von herausragenden
Forscherpersönlichkeiten der verschiedenen Colleges der University of London und von Cancer
Research UK stützen, die das Forschungssprogramm bereichern und ihre Expertise in den Dienst
des GRK stellen werden.
3
INTRO
1.5.2 Summary in German
Zusammenfassend wird das GRK hochqualitative Forschungsprojekte durchführen und die
DoktorandInnen zur interdisziplinären Zusammenarbeit im Kampf gegen den Hautkrebs anleiten.
Das GRK wird gerade durch die Verknüpfung von Grundlagenforschung und kliniknaher
Ausbildung seine Ziele bei der Entwicklung neuer Therapien beim Hautkrebs erreichen können.
1.6 Funding period
01.04.2015-30.09.2019
1.7 Number of PhD and MD positions
For a clinical subspecialty such as Dermato-Oncology, it is highly important to attract enthusiastic
young scientists and to stimulate them to develop a long-term scientific career and ultimately an
independent basic research agenda in the field. In addition, future clinical researchers in DermatoOncology will tremendously profit from additional expertise in the basic sciences. Therefore, the
integration of both PhD and MD students into the RTG will be strongly supported. The interaction
between PhD students and MD students will foster the mutual understanding between basic and
translational research in Dermato-Oncology. MD students will bring a clinical twist into the RTG
and help the PhD students with whom they work together to get a complete picture of the clinical
background and specific questions of their projects. At the same time the PhD students will ensure
transfer of knowledge and efficient training of MD students in a broad spectrum of basic research
approaches and methodologies. As MD students who are willing to devote 1 year to experimental
work in the laboratory are the exception rather than the rule, the RTG will restrict the number of MD
fellowships to recruit only outstanding MD students with the goal of an academic career.
Within the RTG, we apply for 12 PhD positions (0.65 TVL E13) within 13 projects over a period of
4.5 years. An additional PhD position will be financed by the DKFZ. Furthermore, a total of 8 MD
fellowships will be funded by the medical faculties of Heidelberg University (5 MFM, 2 MFH) and
the DKFZ (1 DKFZ) with a stipend of € 670,-- per month.
Associated PhD and MD students. As all the applicants’ laboratories have research programs
with a focus on skin cancer, a conservative estimate is that one associated PhD/MD student from
each lab will participate in the RTG, making up a total of 13 associated student members. The
associated researchers / lecturers will recruit additional associated PhD/MD students into the RTG.
2
Profile of the Research Training Group
INTRO
Heidelberg University and the German Cancer Research Center (DKFZ) together have developed
a joint research and structural focus in the field of Dermato-Oncology. The departments of
Dermatology in Heidelberg and Mannheim, the Clinical Cooperation Unit Dermato-Oncology of the
DKFZ in Mannheim as well as the Department of Signal Transduction and Growth Control of the
DKFZ make up the core of this Mannheim-Heidelberg Skin Cancer Alliance. Additional groups from
both faculties and the DKFZ that have a major research interest in skin cancer biology further
enhance and complement the consortium, including the Department for Vascular Biology and
Tumor Angiogenesis, and the Division of Signaling and Functional Genomics. As skin cancer
constitutes a world-wide health issue of increasing importance due to environmental factors and
the aging population, the Dermato-Oncological Community in Heidelberg/Mannheim has
committed itself to improve research, intensify scientific collaboration and attract young
researchers to this evolving field.
In order to prepare the RTG application, a Steering Committee convened consisting of Prof. Dr. H.
Augustin, Prof. Dr. P. Angel, Prof. Dr. M. Boutros, Prof. Dr. A. Enk, Prof. Dr. S. Goerdt, Prof. Dr. M.
Leverkus, Prof. Dr. S. Schneider, and Prof. Dr. J. Sleeman. After announcement of the planned
RTG, 21 project proposals were submitted. Of these, 13 were selected for the RTG application. In
6 projects, brilliant younger scientists who are in the process of becoming independent group
leaders were recruited as PIs to take project responsibility in the RTG early in their careers. These
scientists will be encouraged to publish the results of their projects as senior authors, while being
mentored by experienced senior scientists to assure successful project guidance. Of the 13
projects, 6 projects are University-based (4 Mannheim, 1 Heidelberg, 1 Mannheim / Heidelberg), 6
are dual University/DKFZ projects, and 1 project is DKFZ-based, resulting altogether in a wellbalanced collaboration between University and DKFZ groups.
4
3
Research Program
3.1 Overview and Aims
Skin cancer is a rising socio-medical and economic threat to patients and the public. Due to
environmental, behavioral, and demographic factors, the incidence of malignant melanoma (MM)
and of non-melanoma skin cancer, especially cutaneous squamous cell carcinoma (SCC), is
continuously rising in Caucasian populations. This is due to the increasing life expectancy and the
intensified sun exposure in Western countries in the second half of the 20th century. SCC develops
in a well-documented multi-step tumorigenesis process induced by UV damage from precursor
lesions to fully malignant tumors. Precursor lesions (p53-mutated “patches”, actinic keratosis or
SCC in situ) may still succumb to cell death and to the body’s own tumor immune responses. Much
less is known about the carcinogenesis of MM, although molecular alterations in oncogenes and
tumor suppressor genes and associated signaling pathways such as e.g. B-Raf may play a major
role. While thin primary MM or SCC are usually treated in a curative manner by skin surgery, thick
primaries have a high potential for loco-regional, lymph node and/or distant metastases that even if
treated by standard therapeutic approaches will result in an unacceptably high mortality. In
addition, treatment of skin cancer is counter-acted by primary resistance to cell death and tumor
immunity. Therefore, there is an increasing need to better understand the mechanisms leading to
skin cancer metastasis and to identify targets to overcome primary resistance.
5
INTRO
The topic of the RTG “Hallmarks of Skin Cancer” is innovative, focused and timely. The research
program of the RTG concentrates on elucidating the hallmarks of skin cancer, especially the
intercommunicative rather than the cell autonomous qualities of tumors, such as cancer cell
dissemination and metastasis as well as primary resistance towards cell death and immunity.
These important topics will be studied with respect to the specifics of skin cancer, i.e. malignant
melanoma and squamous cell carcinoma. Thus, the title of the RTG “Hallmarks of Skin Cancer –
Cancer Cell Dissemination, Primary Resistance, Novel Targets” well reflects the focus of the
research program of the RTG. To guarantee coherence within the RTG research program and to
further enhance collaboration within in the RTG, the two major research areas, i.e. Cancer Cell
Dissemination (A) and Primary Resistance (B), were subdivided into 4 project packages with 3-4
single projects relating to certain hallmarks of skin cancer, i.e Cancer Stem Cells (A1), Invasion
and Metastasis (A2), Primary Resistance to Cell Death (A3), and Primary Resistance to Tumor
Immunity (A4). As a cross-sectional aim, all projects have committed themselves to inherently
direct their research towards the identification and validation of novel therapeutic targets.
With respect to the teaching and qualification program, the areas covered by the projects allow for
a sound interdisciplinary training of the graduate students. All participating laboratories have an
impressive track record in skin cancer research and have proven their potential for innovative
research by high quality publications. The combination of clinical disciplines with basic research
laboratories guarantees sound experimental approaches with a clear translational focus. The study
program of the RTG will profit from the collaboration with the Life Science Graduate Schools of
Heidelberg University (Hartmut Hoffmann-Berling International Graduate School of Molecular and
Cellular Biology (HBIGS)) and of the German Cancer Research Center (Helmholtz International
Graduate School for Cancer Research (HIGS)). HBIGS will be responsible for teaching and
training the PhD/MD students in general molecular and cellular biology and in “soft skills”, whereas
HIGS will be responsible for the teaching program in cancer biology and general oncology. The
RTG will provide added value for the PhD/MD students by applying the general principles and
approaches of cancer biology and oncology (the hallmarks of cancer) to the specific problems and
questions of skin cancer biology and dermato-oncology (the hallmarks of skin cancer). Beyond the
structured study program that accompanies the thesis work of every doctoral student, the
collaboration with the St. John’s Institute of Dermatology in London, UK, and with an interinstitutional, University of London and Cancer Research UK-based faculty guarantees the
internationality of the RTG and allows students as well as supervisors to have their scientific
project approaches cross-checked by high ranked foreign researchers.
Altogether, the innovative research program, the support by the Heidelberg Mannheim Skin Cancer
Alliance, the high qualification of the participating researchers and the high-ranking international
scientific collaboration will help the RTG live up to the high goals of a DFG-funded RTG program.
Hanahan and Weinberg have claimed that six hallmarks of cancer are important for all malignant
tumors including proliferation (mutations of oncogenes), evading growth inhibition (mutations of
tumor suppressor genes), replicative immortality, invasion and metastasis, angiogenesis, and
resistance to cell death. The former three hallmarks of cancer are executive, i.e. they occur within
the cell and bestow the cancer cell with cellular autonomy. The latter three hallmarks are
intercommunicative, i.e. tumorigenesis is supported by interactions of the cancer cell with noncancer cells. Recently, Hanahan and Weinberg have delineated two more executive hallmarks of
cancer (genome instability and mutation, cellular energetics) and two more intercommunicative
hallmarks of cancer (tumor immune escape, tumor-promoting inflammation). They especially
emphasize (1) that it is necessary to analyze the significance of any hallmark of cancer in the
context of a specific tumor entity, and (2) that the importance of the tumor microenvironment is
becoming increasingly apparent. Therefore, the RTG (1) proposes to analyze hallmarks of skin
cancer, and (2) focuses on intercommunicative hallmarks and the tumor microenvironment.
Thus, the research program of the RTG aims to elucidate the cellular/molecular pathways that lead
to skin cancer cell dissemination (Research Area A), and to analyze the mechanisms of primary
skin cancer resistance to cell death and tumor immunity (Research Area B). In a cross-sectional
approach, all projects aim to identify novel targets against the hallmarks of skin cancer they study.
INTRO
3.1.1 Research Area A – Cancer Cell Dissemination
Project Package A1: Cancer Stem Cells (Projects 1-4)
Project Package A2: Invasion and Metastasis (Projects 5-7)
The processes leading to skin cancer dissemination and metastasis are complex and far from
being completely understood. The RTG will therefore aim to investigate in depth the molecular and
cellular mechanisms of skin cancer dissemination and metastasis (Projects 1-7). As in other
cancers, metastasis in MM and SCC follows an ordered sequence of events. However, the MMand SCC-specific molecular and cellular determinants of these events may vary as predicted by
the “seed and soil” hypothesis, and only a minor population within all tumor cells seems to be
involved in metastasis. The concept of cancer stem cells (CSC) and their potential plasticity is
therefore of great importance. Counter-intuitively, CSC may already acquire invasive potential and
metastasize early during tumorigenesis, causing the phenomenon of tumor dormancy. CSC may
orchestrate different waves of cancer cell dissemination from the primary as well as from different
distant metastatic foci and may even re-colonize the primary (Projects 1-3). As a precondition for
dissemination, MM and SCC cells have to acquire enhanced cell motility and invasive capacity that
is regulated by signaling pathways (Project 3, 4) and mediated by adhesion molecules (Project 5).
These steps are followed by intravasation and transit via the blood vascular or lymphatic systems.
The circulating tumor cells need to be arrested intravascularly at the site of metastatic colonization,
e.g. by binding to coagulation factors deposited on the luminal side of the vessel wall (Project 6) or
by binding to organ-specific endothelial adhesion molecules (Project 7). Subsequently, tumor cells
must extravasate and finally grow at the distant site. During this phase, the tumor cells need strong
survival mechanisms, and must resist immune surveillance (Research Area B).
3.1.2 Research Area B – Primary Resistance to Cell Death and Immunity
Project Package B1: Primary Resistance to Cell Death (Projects 8-10)
Project Package B2: Primary Resistance to Tumor Immunity (Projects 11-13)
Programmed cell death by apoptosis has been recognized as an important barrier towards the
development of various cancers. Conversely, compelling evidence has accumulated that
resistance to cell death occurs in malignant tumors as they develop into high grade malignancies,
and accompanies resistance to treatment in general. Resistance to cell death has been shown to
develop in both MM and SCC. However, the first therapeutic trials with drugs blocking Bcl-2 familiy
members have failed, indicating the need for a better understanding of cell death resistance in skin
cancer. Programmed cell death is a sophisticated multi-facetted process. The RTG research
program includes three projects dealing with new aspects of programmed cell death. Project 8
investigates protection of MM cells against anoikis, a special form of apoptosis caused by
inadequate tumor cell-matrix interactions that may be targetable for therapy by angiopoietin-2
antagonists/antibodies. Project 9 analyzes a novel form of programmed cell death in SCC called
programmed necrosis or necroptosis, and its regulation by the ripoptosome, a newly identified
6
subcellular cell death-associated platform. Finally, project 10 examines the potential of a novel
class of small molecules called IAP antagonists to overcome resistance to cell death in MM.
An important form of eradication of incipient neoplasias, late-stage tumors or micrometastases is
immune-mediated cell death. Immunosurveillance is active in skin cancer in both SCC and MM as
immunocompromised patients; for example, show a tremendous tendency to develop high grade
SCC. However, immunosurveillance seems to be effective only in incipient SCC; with progression,
SCC and MM develop mechanisms of tumor immune escape or even hi-jack the immune system
for their needs. Project 11 will analyze the role of the chemokine receptor CCR6 in
immunosurveillance of MM. Project 12 will study how pro-inflammatory cytotoxic dendritic cells
may be used to re-direct the host immune system towards efficient immunological tumor cell killing.
Finally, there is a growing body of evidence that tumor-associated myeloid cell populations are
educated by the tumor itself to support tumor growth and metastasis (Project 13).
3.1.4 Collaboration, Methods, Model Systems
Within the RTG, the projects will intensively collaborate. Examples are the transfer of novel targets
to unique model systems, such as mouse models (Project 5,13), human skin cancer stem cell
models (Project 1,2), and imaging (Project 6). The details of the collaborative interactions between
the projects are outlined in the project descriptions. The experimental methods used include
molecular and cell culture techniques, state-of-the-art gain- and loss-of function approaches
including CRISPR/Cas9 genome editing, large scale RNAi screening, novel model systems in
human cells, and additional cutting edge technologies in skin cancer research. Furthermore,
animal models including the ret transgenic MM mouse (e.g. Projects 6,7,13), the well-established
DMBA/TPA SCC model (Project 5), and the transgenic K5-SOS-F transgenic mouse are available.
As a result, a broad spectrum of molecular, genetic, biochemical, cell biological, histological and
morphometrical techniques will be ready to use within the RTG. The entire RTG including the
associates will benefit from this expertise, both in terms of education and in terms of competitive
research.
7
INTRO
3.1.3 Novel Targets – A Cross-sectional Approach
Targeting known molecular and cellular events that regulate tumor progression and metastasis in
MM and SCC has led to remarkable therapeutic advances in the recent years. Unfortunately, these
treatment modalities provide only short term clinical remissions due to secondary resistance
development. As a result, there is a need to identify additional targets for tumor progression,
metastasis, and primary tumor cell resistance to hit skin cancer with combination therapies before
secondary tumor cell resistance has developed. Therefore, the identification of novel targets in skin
cancer will be a cross-sectional focus of the RTG. Several projects will investigate tumor-specific
targets in MM or SCC, including podoplanin or Wnt in invasion by SCC (Project 4,5), molecules
mediating intravascular MM cell arrest (Projects 6,7), the inhibition of cell death pathways in MM
and SCC (Projects 8-10) and the generation of cytotoxic dendritic cells (Project 12). In order to
validate novel targets, human model systems of the metastatic process are needed (Project 6).
The combination of projects covering individual targets with other projects that develop innovative
methodology will allow novel targets to be directly tested synergistically within the framework of the
RTG.
3.2 Project Descriptions
Project Package A1: Cancer Stem Cells (Projects 1-4)
Project 1: The role of Id proteins in determining the tumor initiating and metastatic
properties of melanoma cells
Principal Investigator:
Prof. Dr. Jonathan Sleeman, CBTM, Medical Faculty Mannheim, Heidelberg University
London Project Partner:
Dr. Caroline Hill, Cancer Research UK, London Research Institute
Short Summary
Cancer stem cells are thought to underpin the growth, metastasis and therapy resistance of tumors
such as melanoma, through their tumor initiating properties. Building on unpublished observations,
this project aims to substantiate the hypothesis that Id gene expression induced by 3D extracellular
matrix (ECM) microenvironments plays a functional role in determining stemness and metastatic
properties of melanoma cells. The role of integrins, TGF-β and BMPs in determining these
properties will be determined. These data should identify new therapeutic targets.
PACKAGE A1
3
State of the Art
3.1 State of knowledge in the field
The concept that the bulk of cells that make up a tumor, including melanomas, are derived from
cancer stem cell (CSC) subpopulations is now widely accepted. CSCs are distinguished from other
tumor cells by their ability to successfully seed new tumors when implanted in low numbers into
experimental animals, and to recapitulate the morphology of the initial tumor. In contrast, the nonCSC population cannot initiate tumor growth in vivo even when implanted in high numbers. The
potential significance of CSCs for cancer therapy is enormous. Current therapies appear to
preferentially destroy the non-CSC population but do not efficiently kill CSCs, with the result that
the tumor eventually regrows. Furthermore, as the CSC subpopulation represents by definition the
only tumor cells that are able to initiate the growth of new tumors, then CSCs must play a central
role in metastasis formation. Understanding the parameters that determine tumor-initiating
properties should therefore identify targets for novel and efficient cancer therapies.
Tumor initiation in vivo is used to define CSCs. Numerous papers have shown that the take rate of
tumors in vivo can be manipulated, for example by coinjecting tumor cells with matrigel. Indeed,
single unsorted human melanoma cells in matrigel are capable of forming tumors in NOD/SCID
Il2rg-/- mice (Quintana et al., 2008, Nature). These observations point to a critical role for the
microenvironment, in particular the extracellular matrix, in determining tumor-initiating properties.
3.2 Preliminary work by the participants
We have a long track record in metastasis research. Recently we have begun exploring the role of
CSCs in metastasis, partly in collaboration with Prof. Umansky (Project 13), with whom we have
published work using the Ret murine melanoma model. In unpublished work we have investigated
the role of ECM components in determining tumor-initiating properties in vivo. As few as 5 cells
from the B16 or Ret murine melanoma cell lines were sufficient to initiate tumor growth when coinjected into syngeneic mice with matrigel. In contrast, tens of thousands of cells were required to
initiate tumor growth in the absence of matrigel. In further experiments we found that co-injection of
tumor cells with laminin or with collagen type I was also sufficient to elicit tumor growth from 5
cells. These data indicate that highly immunocompromised mice are not required for tumor
initiation from just a few cells, and that several ECM components are able to initiate tumor growth
from small numbers of melanoma cells, all of which are ligands for β1-containing integrins.
Microarray analysis revealed that Id1, Id3 and Smad6, archetypal TGF-β/BMP response genes,
were uniquely upregulated (up to 40-fold) in response to 3D but not 2D ECM (matrigel, collagen or
laminin), a finding confirmed using qPCR. Id genes are known to play a pivotal role in regulating
tumor growth and determining stemness properties, while Smad6 counter-regulates TGF-β/BMP
8
signalling. We also found that tumor cells that do not respond to 3D ECM by upregulating Id1 and
Id3 do not show efficient tumor initiation when co-injected with matrigel in vivo. Collaborative work
with Prof. Utikal (Project 2) has shown that human melanoma cells can also respond to 3D matrix
by upregulating Id1, Id3 and Smad6.
4.2 Experimental program
Aim 1: We will establish loss of function (shRNA, cannabidiol chemical inhibition) and gain of
function (tet-inducible expression) for Id1 and Id3 (either alone or in combination) in B16 and Ret
melanoma cells. We will then test the cells for their tumor initiating and metastatic ability in vivo in
the presence (loss of function) or absence (gain of function) of matrigel. These data will
demonstrate whether Id1 and Id3 induction in 3D ECM plays a role in specifying the tumor-initiating
and metastatic properties of melanoma cells.
Aim 2: We will use loss of function (shRNA) and gain of function (constitutively active mutant)
approaches to determine whether β1-containing integrins are involved in the induction of Id1, Id3
and Smad6 in response to 3D ECM microenvironments. If so, we will determine using B16 and Ret
cells whether loss of β1 ablates efficient tumor initiation in vivo in the context of 3D ECM, and what
effect it has on metastasis. Conversely, we will establish whether constitutively activated β1
integrin supports efficient tumor initiation in vivo even in the absence of a 3D ECM matrix, as well
as whether it promotes metastasis formation.
Aim 3: We will determine which members of the TGF-β and BMP families and their receptors are
expressed in B16 and Ret cells growing in 3D ECM environments. For those that are expressed,
we will use shRNA to knockdown their expression, and/or use specific inhibitors of TGF-β and
BMP signalling to block their activity, then determine whether this affects the ability of 3D ECM to
induce Id1, Id3 and Smad6 expression, and to promote efficient tumor initiation in vivo. Effects on
metastasis formation will also be determined. We will also investigate whether 3D ECM
environments promote Id1, Id3 and Smad6 expression by sequestering TGF-β and BMP family
members produced by the melanoma cells at locally high concentrations in the ECM around the
cells. For all aims, the results of the experiments will be corroborated in human melanoma cells to
demonstrate relevance to human disease.
4.3 Collaborations with other projects in the RTG: Collaborations with Prof. Utikal (Project 2)
will include (i) isolation of CSC marker-enriched subpopulations from human melanoma samples
and analysis of their Id protein expression (ii) analysis of Id expression in primary human
melanomas and their metastases. Collaborations with Projects 5 and 7 comprise provision of
antibodies, genetically modified mice, and expertise in techniques such as the analysis of cell
interactions with hyaluronan and lymphangiogenesis.
5
References
1. Müller T, Stein U, Poletti A, Garzia L, Rothley M, Plaumann D, Thiele W, Bauer M, Galasso A, Schlag P, Pankratz M,
Zollo M, Sleeman JP. 2010. ASAP1 promotes tumor cell motility and invasiveness, stimulates metastasis formation
in vivo, and correlates with poor survival in colorectal cancer patients. Oncogene 29:2393–2403
2. Neeb A, Wallbaum S, Novac N, Scholl I, Dukovic-Schulze S, Schreiber C, Schlag P, Moll J, Stein U, Sleeman JP.
2012. The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of
colorectal carcinoma patients. Oncogene 31:3796-806
3. Kuch V, Schreiber C, Thiele W, Umansky V, Sleeman JP. 2013. Tumor initiating properties of breast cancer and
melanoma cells in vivo are not invariably reflected by spheroid formation in vitro, but can be increased by long-term
culturing as adherent monolayers. Int J Cancer 132:E94-105.
9
PACKAGE A1
4.
Project Plan
4.1 Specific Aims: (1) To test the hypothesis that Id1 and Id3 expression induced in 3D ECM
microenvironments plays a functional role in determining the tumor initiating and metastatic
properties of melanoma cells; (2) To determine whether β1-containing integrins mediate 3D ECMmediated upregulation of Id1, Id3 and Smad6, and are required for efficient tumor initiation and
metastasis formation in vivo; (3) To investigate whether TGF-β and/or BMP signalling mediates
increased Id1, Id3 and Smad6 in 3D ECM microenvironments.
Project 2: Characterization of human melanoma cells on the
basis of markers of pluripotent stem cells
Prof. Dr. Jochen Utikal, Skin Cancer Unit, German Cancer Research Center and Department of
Dermatology, Venereology and Allergology, University Medical Center Mannheim,
Ruprecht-Karl University of Heidelberg
Prof. Fiona Watt, Centre for Stem Cells and Regenerative Medicine, King’s College, London
Short Summary
Embryonic stem cells (ES cells) are similar to melanoma cells in many aspects. ES cells are
immortal and proliferate rapidly. They also form tumors (teratomas) when transplanted into
immune-deficient mice. Similar to ES cells melanoma cells show also a plasticity. By the ectopic
overexpression of different sets of transcription factors or microRNAs somatic cells can be
converted into ES-like cells.
Our studies indicate that melanoma comprise different subpopulations which express marker of
pluripotent stem cells (e.g. Nanog, Sox2). The projects objective will be to identify such
subpopulations within murine and human primary melanoma cells as well as in melanoma cell
lines. Respective subpopulations will be analyzed at the genomic, epigenomic, and proteomic
level. Functional abilities for maintaining the tumor cell growth will be tested. Moreover, the
accessibility of different subpopulations towards cellular reprogramming, the reprogramming
kinetics and factor requirements will be investigated. This project should help to understand the
maintenance and formation of melanomas. The examined markers might serve as therapeutic
targets in future.
3
State of the Art
Embryonic stem cells (ES cells) are similar to tumor cells in many aspects. ES cells are immortal
and proliferate rapidly. They also form tumors (teratomas) when transplanted into immune-deficient
mice.
PACKAGE A1
We have shown that different cell types including mouse and human melanocytes or melanoma
cells can be reprogrammed into pluripotent stem cells by the ectopic expression of transcription
factors such as Oct4, Klf4, Sox2 and c-Myc. These pluripotent stem cells have all the features of
ES cells including immortal growth, the expression of pluripotency markers (e.g. Sox2 and Nanog)
and the potential of forming teratomas (Stadtfeld et al., 2008; Eminli et al., 2008; Utikal et al.,
2009a). The conversion efficiencies of melanocytes into pluripotent stem cells can be increased
dramatically by downregulating p53 or p16/p19 further underscoring similarities of this mechanism
with tumorigenesis (Utikal et al., 2009b). Our preliminary studies show that subpopulations of
human melanoma cells reveal an endogenous expression of pluripotency markers such as Nanog
or Sox2. However, these cell populations are not yet well characterized and their functional abilities
for maintaining the tumor cell growth are not yet known.
4
Project Plan
4.1 Specific Aims
Main hypothesis: Markers of pluripotent stem cells play a main role in development and
maintenance of human malignant melanoma
Aim 1: Identification of cell populations which express markers of pluripotent stem cells (e.g. Sox2,
Nanog) in murine and human primary melanoma cells and melanoma cell lines.
Aim 2: In-depth analysis and comparison of expression profile and epigenetic status as well as
functional analysis of different subpopulations.
10
4.3 Collaborations with other Projects in the RTG
For the analysis of melanoma subpopulations at the genomic, epigenetic, and proteomic level, we
will closely collaborate with projects 1 and 4. Functional abilities for initiating and maintaining tumor
cell growth will be tested in cooperation with project 10. The ret transgenic mouse model of
malignant melanoma will be provided by project 13.
5
References
1. Eminli S*, Utikal J*, Arnold K, Jaenisch R, Hochedlinger K. 2008. Reprogramming of neural progenitor cells into
induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cells 26:2467-74. * authors
contributed equally
2. Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. 2008. Induced pluripotent stem cells generated without
viral integration. Science 322:945-9.
3. Utikal J, Maherali N, Kulalert W, Hochedlinger K. 2009. Sox2 is dispensable for the reprogramming of melanocytes
and melanoma cells into induced pluripotent stem cells. J Cell Science 122:3502-10.
4. Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, Khalil A, Rheinwald JG, Hochedlinger K. 2009.
Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460:1145-8.
11
PACKAGE A1
In order to identify subpopulations of melanoma cells expressing common markers of pluripotent
stem cells such as Sox2 or Nanog lentiviral reporter constructs will be generated. Reporter
constructs will be designed such that the promoter of a particular pluripotency marker will control
the co-expression of a fluorescing (e.g. GFP) and an antibiotic selection marker. Lentiviral particles
carrying the reporter constructs will be produced and purified.
Primary melanoma cells directly isolated from patients, from our established transgenic RET
melanoma mouse model as well as cells from melanoma cell lines (e.g. C32, HT144) will be
infected with lentiviral vectors that carry the reporter constructs. Cells expressing the respective
genes and accordingly also expressing the fluorescent marker will be visualized by means of
fluorescent microscopy. Quantification and separation of fluorescently labelled Sox2- and Nanogexpressing melanoma cells will be done by fluorescence activated cell sorting. This will also enable
to monitor if cells from a certain subpopulation have a stable phenotype or might perhaps convert
to cells from a different subpopulation.
The sorted populations will be compared by analysing the expression of additional stem cell
markers, global gene expression and DNA methylation in detail. Immunofluorescent labeling will be
performed to examine the expression of markers (e.g. Sox2, Nanog, SSEA-3/4, Lin28) and
melanoma-specific markers (e.g. S100, MART-1, HMB-45, MITF), respectively. For the evaluation
of differential gene expression DNA microarrays and RT-PCR will be performed. Moreover, the
promoter methylation status of stem cell- and melanoma-associated genes as an indicator for
transcriptional activity will be checked by bisulfite sequencing.
To correlate the afore mentioned parameters with functional properties, the tumorigenic potential of
subpopulations will be investigated. For this purpose, the cells will be injected subcutaneously into
immune-deficient mice (in the case of human cells) or in the syngenic RET transgenic melanoma
mouse model (mouse melanoma cells) and tumor growth will be quantified. By knocking down the
expression of melanoma- and pluripotency-associated genes with shRNA, the role of these genes
for tumor development and growth will be studied. The impact of different subpopulations on tumor
development will be analyzed by specifically depleting those cells. This will be achieved by
infecting melanoma cells with a lentiviral construct that contains a promoter (e.g. Nanog or Sox2
promoter) which controls the expression of the enzyme thymidine kinase. Application of ganciclovir
will selectively deplete all cells which express thymidine kinase. Tumor growth in the absence and
presence of different subpopulations will be compared and marker switching abilities of tumor cells
will be investigated. Another functional aspect we will focus on is the amenability of melanoma
subpopulations to the process of reprogramming by transcription factors such as ectopic Oct4, Klf4
and c-Myc. Reprogramming kinetics and factor requirements will be determined.
Project 3: The role of Wnt signaling in tumor-initiating cells and
tumor progression in cutaneous SCC
Dr. Iris Augustin, Prof. Dr. Michael Boutros, Div. of Signaling and Functional Genomics DKFZ,
and Dept. Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University
Prof. Fiona Watt, Centre for Stem Cells and Regenerative Medicine, King’s College, London
Short Summary
The project is aimed at deciphering the role of autocrine and paracrine Wnt signaling in squamous
cell carcinoma (SCC). To investigate the role of the Wnt ligands in papilloma formation and their
progression to carcinomas, we will selectively ablate the Wnt secretion factor Evi in skin SCC cell
lines and in keratinocytes of adult mice. The role of Evi in SCC will be addressed in cell-based
assays as well as in transplantation experiments. To genetically manipulate Evi during SCC
tumorigenesis, we will target different cellular compartments of the skin epidermis crossed with
KRasLSL-G12D and TP53fl/fl mice as well as with Evifl/fl mice to dissect the contribution of Wnt
signaling to tumor initiation and malignancy in IFE- and HF-derived cutaneous SCC. The project
will thereby provide insights in cellular signal transduction controlling skin carcinogenesis.
PACKAGE A1
3
State of the Art
Keratinocyte-derived non-melanoma skin cancers (NMSC) comprising basal cell (BCC) and
squamous cell carcinoma (SCC) are the most common malignancies. SCCs are locally invasive
and acquire the ability to metastasize, making them suitable models to study tissue invasion and
metastasis. SCC development follows a multi-step model of tumorigenesis including Ras and p53
mutations, and they may derive either from adult interfollicular (IFE) or follicular (HF) tumorinitiating cells (TIC). Wnt signaling is critically involved in tumor initiation and progression of various
types of tumors including the fate of TICs. Yet, the downstream mechanisms of SCC tumorigenesis
involving Wnt signaling have not been unraveled. Beta-catenin deletion suppresses TICs in SCC
and induces tumor regression. Invasive SCC is also marked by the concurrent upregulation of ßcatenin-independent and repression of ß-catenin-dependent Wnt signaling. As such, it has been
shown that Wnt5a gradients enhance directed motility of keratinocytes. Wnt5a deficiency
suppresses tumor growth of human malignant HaCaT-II4 cells. Yet, the downstream mechanisms
of SCC tumorigenesis involving Wnt signaling have not been unraveled.
3.2 Previous work by the participants
Previous work of the applicant addressed the contribution of Wnt signaling in developmental and
pathological conditions. The research focused on the Wnt secretion factor Evi/Wls. Evi is required
for the secretion of all Wnt ligands and therefore essential for pan Wnt signaling cascades.
Manipulating Evi function in a time- and cell type-specific manner represents a versatile tool to
study autocrine and paracrine Wnt signaling in different biological contexts. Experiments on
glioblastoma revealed an important role of Evi in glioma tumorigenesis (Augustin et al., 2012).
Furthermore, we generated transgenic mouse lines, conditionally Evi-deficient or ectopically
overexpressing Evi. These mice were analyzed regarding Evi function in skin homeostasis.
Targeted deletion of Evi in keratinocytes revealed aberrant skin morphology together with
enhanced immune cell recruitment, which closely resembled human psoriatic skin disorders
(Augustin et al., 2013).
12
4
Project Plan
4.1 Specific Aims
The proposed project is aimed at pursuing the following specific aims:
1. What is the role of Wnt secretion in malignant epidermal tumor initiation and progression?
2. What is the mechanistic contribution of Wnt secreting tumor cells in the maintenance of
cutaneous tumor initiating cells (TIC)?
Mouse model studies will be performed in collaboration with project 5. We will work with project 4
on the role of Wnt signaling in melanoma cells and with project 9 on SCC biology. We will study
angiogenesis in resulting tumors in collaboration with project 8.
5
References
1. Augustin I, Gross J, Baumann D, Korn C, Kerr G, Grigoryan T, Mauch C, Birchmeier W, Boutros M. 2013.
Psoriasiform dermatitis-related phenotype caused by loss of epidermal Wnt secretion. J Exp Med 26:1761-77
2. Voloshanenko O, Erdmann E, Dubash T, Augustin I, Metzig M, Hundsrucker C, Kerr G, Sandmann T, Anchang B,
Demir K, Boehm C, Leible, Ball C, Glimm H, Spang R, Boutros M. 2013. Wnt secretion is required to maintain high
levels of Wnt activity in colon cancer cells. Nat Commun 4:2610
3. Augustin I, Goidts V, Bongers A, Kerr G, Vollert G, Radlwimmer B, Hartmann C, Herold-Mende C, Reifenberger G,
von Deimling A, Boutros M. 2012. The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis. EMBO
Mol Med 4:38-51
13
PACKAGE A1
Aim 1: Our previous results have shown that epidermally secreted Wnt ligands play important roles
in skin homeostasis. In order to determine Evi function in malignant tumor growth, we will generate
Evi-deficient murine SCC cell lines (BDVII, PDVA) by CRISPR/Cas9 technology and characterize
their proliferation and mobility. Transwell experiments will be performed to analyze tumor cell
migration and invasiveness. In order to determine the paracrine effect of Wnt secreting stromal
cells on the migratory and invasive growth of SCC cells, Transwell co-culture assays with Evioverexpressing MEFs (Wnt-on) as well as Evi-deficient MEFs (Wnt-off) will be compared.
Subcutaneous injection of these SCC cells in mice will be performed to analyze tumor growth,
morphology and invasive behavior. Epidermal deficiency of Evi impairs the cross talk between
keratinocytes and immune cells (Augustin et al., 2013). Therefore, transplantation of SCC cells in
syngeneic and immune competent recipients will provide an additional tool to study tumor immune
cell infiltration.
Aim 2: To genetically manipulate Wnt signaling during SCC tumorigenesis in vivo, we will use hairfollicle-specific (K19creER) and inter-hair-follicle-specific (INVcreER) driver mice crossed with
KRasLSL-G12D and TP53fl/fl mice as well as with Evifl/fl mice to dissect the contribution of Wnt
signaling to tumor initiation and malignancy in IFE- and HF-derived cutaneous SCC. In order to
decipher the role of Wnt secretion on TIC maintenance, TICs will be analyzed from multiple Evi
loss-of-function transgenic animals. FACS-based isolation of TICs (CD34high/EpCAMhigh) will be
performed and the cells will be expression-profiled. TIC transcript signatures provide insights in
Wnt-dependent TIC signaling networks.
This project will apply complex mouse genetics to study the role of Wnt secretion in TICs. The
indicated experimental setup schedules the investigation of Evi function in malignant SCC cell lines
prior the transgenic mouse studies. Therefore, the time for the breeding procedure is
experimentally covered by the analyses of SCC cell line in transplantation and cell-based assays.
Project 4: Identification of genes linked to aberrant Wnt secretion in melanoma
Prof. Dr. Michael Boutros, Div. of Signaling and Functional Genomics DKFZ, and Dept. Cell and
Molecular Biology, Medical Faculty Mannheim, Heidelberg University
Prof. Frank Nestle, St John's Institute of Dermatology, King’s College, London, and
Prof. Buzz Baum, Laboratory for Molecular Cell Biology, Medical Research Council, University
College London
Short Summary
Wnt signaling has been implicated in multiple stages of melanoma tumorigenesis. Recently, it has
been shown that downregulation of Evi/Wls, the cargo-receptor for all Wnt ligands, has a profound
effect melanoma cell proliferation and metastasis. Concordantly, melanoma biopsies showed a
decrease in Evi levels and low levels of nuclear β-catenin. Here, we propose to dissect the cellular
processes that are influenced by aberrant Evi levels in melanoma cells. We will perform genomescale RNAi screens to identify genetic interactors of Evi which act as synthetic lethals with loss-of
or gain-of function Evi. We will further characterize these genes by biochemical and cell-biological
methods. In addition, we will analyse the role of Wnt secretion of the microenvironment of
melanoma cells ex vivo and in transgenic mouse models for melanoma in vivo.
PACKAGE A1
3
State of the Art
Wnt proteins are secreted morphogens that regulate key processes during development and
homeostasis. Aberrant regulation by means of overexpression of ligands or signal transducers has
been linked to many cancers. The secretion of Wnt ligands depends on the Wnt-specific cargoreceptor Evi/Wls which binds to Wnt proteins in the Golgi and is required for its transport to the
plasma membrane and exocytosis (Bartscherer et al., Cell 2006). Evi is a cargo-receptor for both
canonical and non-canonical Wnt ligand secretion and has been recently shown to be upregulated
in glioma and required for glioma cell proliferation, migration and tumor initiation (Augustin et al.,
EMBO Mol Med 2012).
Wnt signaling is implicated in the progression and metastasis of melanoma. Normal skin and
benign nevi express several Wnt proteins (Wnt2, Wnt5a, Wnt7b, Wnt10b) which are
downregulated in melanoma. In particular, decreased levels of canonical Wnt signaling has been
correlated with a poor outcome. Concordantly, it was recently shown that loss-of Evi expression in
melanoma cells leads to an increase in cell proliferation and metastasis (Yang et al., EMBO Mol
Med 2012), however, the exact molecular mechanism remains poorly understood.
The Wnt cargo-receptor Evi was first discovered in our laboratory in a genome-wide RNAi screen
in Drosophila (Bartscherer et al., Cell 2006) and has subsequently shown to have a conserved
function in Wnt signaling throughout the animal kingdom. Evi is a specific cargo-receptor to Wnt
proteins, as other signaling routes appear not to be affected. Deletion of Evi during mouse
development leads to early embryonic phenotypes similar to Wnt3a. We have recently shown that
Evi is overexpressed in astrocytic glioma and promotes glioma tumorigenesis (Augustin et al.,
2012). Interestingly, while Evi acts as an oncogene in glioma, it has a tumorsuppressor function in
melanoma, indicating context-specific roles, e.g. in the balance between canonical and noncanonical Wnt signaling. To study tissue-specific role of Wnt secretion in vivo, we have generated
conditional Evi loss-of-function (Evi-LOF) and Evi overexpression transgenic (Evi-GOF) mice. EviK14-Cre knockout mice display, in addition to impaired hair follicle morphogenesis, an inflamed
skin and prominent neutrophil infiltration followed by T cell recruitment, leading to chronic
inflammation.
14
4
Project Plan
4.1 Specific Aims
This project has two overall aims: (1) we intend to dissect the cell-autonomous regulatory circuits
that contribute to Evi mediated proliferation and metastasis in melanoma. To this end, we will
perform genetic interaction screens using melanoma cell lines that have either low or high levels of
Evi expression, searching for genes that act synergistically or antagonistically with Evi expression.
(2) We will analyze the identified candidate genes by biochemical and cell-biological methods. We
are particular interested in genes that dysregulate Evi expression or act downstream to influence
cell proliferation and metastasis. Taken together, these studies should provide a better
understanding on the role of Wnt ligands and their downstream signaling during melanoma
tumorigenesis.
We will work with Project 4 on the role of Wnt signaling in melanoma cells. We further collaborate
with project 9 (Leverkus) and 10 (Geserick/Leverkus) on high-throughput RNAi analysis and
CRISPR/Cas9 technology.
5
References
1. Gross JC, Chaudhary V, Bartscherer K, Boutros M. 2012. Active Wnt proteins are secreted on exosomes. Nat Cell
Biol 14:1036-45
2. Augustin I, Goidts V, Bongers A, Kerr G, Vollert G, Radlwimmer B, Hartmann C, Herold-Mende C, Reifenberger G,
von Deimling A, Boutros M. 2012. The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis. EMBO
Mol Med 4:38-51
3. Horn T, Sandmann T, Fischer B, Axelsson E, Huber W, Boutros M. 2011. Mapping of signalling networks through
synthetic genetic interaction analysis by RNAi. Nature Methods 8:341-6
4. Buechling T, Chaudhary V, Spirohn K, Weiss M, Boutros M. 2011. p24 proteins are required for secretion of Wnt
ligands. EMBO Rep 1:1265-72.
5. Bartscherer K, Pelte N, Ingelfinger D, Boutros M. 2006. Secretion of Wnt ligands requires Evi, a conserved
transmembrane protein. Cell 5:523-33.
15
PACKAGE A1
Aim 1: In order to identify synthetic genetic interactions (synthetic lethals) of Evi melanoma, we will
conduct genome-scale RNAi screens using A375 and A2058 melanoma cell lines. Using
CRISPR/Cas9 technologies, we will create isogenic cell lines that have high or low levels of Evi
expression. Using high-throughput microscopy, we will score a range of phenotypes, including cell
proliferation and viability, but other changes in overall cell morphology. This will be done in
collaboration with the lab of Buzz Baum who is an expert in systems analysis of signaling and cell
shape. Computational analysis will be performed as described in Horn (2011). Pathway specific
analyses of identified candidate gene will indicate signaling circuits and might open the possibility
to test selective inhibitors.
Aim 2: Identified candidates will be validated and further studied to understand their biological role
in cells and using mouse models in vivo. We expect that candidate genes can act as epigenetic
repressors of Evi expression in melanoma or restore canonical Wnt signaling downstream of Wnt
secretion. For epigenetic regulators, we will perform ChIP experiment to test whether they act on
enhancers in the Evi locus. We will assess whether regulators of Evi expression are similarly
dysregulated in melanoma. Candidate genes acting downstream of Wnt secretion will be analyzed
for their activity in canonical and non-canonical signaling branches and will assess their effect on
cell proliferation and metastasis ex vivo and in vivo.
Project Package A2: Invasion and Metastasis (Projects 5-7)
Project 5: Function of the mucin-like glycoprotein podoplanin in squamous cell
carcinoma progression
Prof. Dr. Peter Angel, Division Signal Transduction and Growth Control, German Cancer
Research Center (DKFZ), Heidelberg
Dr. Joy Burchell, Research oncology KCL, Guy's Hospital, London
Short Summary
The mucin-like glycoprotein podoplanin (PDPN) represents a tumor-associated protein in a variety
of tumors including squamous cell carcinoma of the skin in mouse and human and correlates with
poor prognosis and metastatic risk. Overexpression of PDPN in pancreatic cancer promoted tumor
cell invasion and affected migration of glioblastoma and keratinocyte cell lines via modulation of
the cytoskeleton pointing to a fundamental role of PDPN in tumor cell migration and invasion. We
will i) measure transcriptional control of PDPN by altered cell death pathways promoting SCC
formation and ii) define the in vivo function of PDPN in SCC. Here, we will apply loss-of-function
approaches in cultured human SCC cells with metastatic potential and measuring parameters of
cell invasion and actin cytoskeleton. Importantly, we will make use of floxed PDPN mice recently
generated in our lab to specifically delete this gene in keratinocytes via K14-Cre transgenic mice.
To unequivocally define the function of PDPN in tumor development and progression, the well
established chemically induced in vivo skin carcinogenesis protocol will be applied to such mice
and tumor cell proliferation, migration and invasion will be determined.
PACKAGE A2
3
State of the Art
Non-melanoma skin cancer, such as basal cell carcinoma (BCC) and squamous cell carcinoma
(SCC) is a very common malignancy. SCC as a solid tumour is composed of transformed
epidermal keratinocytes with a highly invasive growth and tendency to metastasize. Both in vitro
and in vivo model systems demonstrated that malignant transfor-mation of epidermal cells is a
multistage process, in which stepwise accumulation of genetic and epigenetic events determines
the transition from normal to malignant cellular state. However, the onset and the order of genetic
alterations that lead to development of most sporadic cancers remain undefined. Mouse skin
carcinogenesis has been an important tool for developing the current concepts regarding human
neoplasia and the multistage nature of tumour development and progression. In fact, some types
of mutation in oncogenes and tumour suppressor genes identified in mouse skin models also occur
in human epithelial cancers. One of the best-defined experimental in vivo systems for epithelial
cancer develop-ment is the chemically induced tumour model of mouse back skin. Treatment of
the skin with the carcinogen 7,12-dimethylbenz-[a]-anthracene (DMBA) and the tumour promoter
12-O-tetradecanoylphorbol-13-acetate (TPA) result in the formation of benign papillomas (PAPs)
and malignant tumours (SCCs). Using this model, the timing of genetic and chromosomal
alterations, as well as the cellular crosstalk between epithelial cells and cells of the
microenvironment (e.g. fibroblasts, endothelial cells and immune cells) that take place during the
different stages of tumour development and progression can be studied.
Using the DMBA/TPA model the central contribution of signal transduction pathways funnelling into
transcription factor AP-1 (Fos/Jun) to premalignant conversion and malignant progression of
epidermal cells was described. Using gene expression profiling from specimens of TPA-treated
back skin and benign and malignant tumours derived from the DMBA/ TPA model we have
identified novel TPA-inducible genes in mouse skin including the mucin-like glycoprotein
podoplanin (PDPN). We identified pdpn as a direct c-Fos target gene being part of a Fosdependent genetic program in both the DMBA/TPA and the genetic K5-SOS-F transgenic skin
16
tumor model exhibiting expression in tumor cells, particularly at the tumor-stroma border. Despite
the i) correlation between pdpn expression and tumor cell invasion, malignant progression and
metastasis in mouse tumor models, as well as poor prognosis and metastatic risk in human
cancer, and ii) accelerated cell motility and invasion in vitro and induced tumor growth in a
xenograft model upon ectopic Pdpn, the role of PDPN in SCC formation and progression have not
been addressed.
1. We will use well-known HaCaT cell lines harbouring additional Ras mutations, which exhibit
high invasive capacity in vitro in 3D skin equivalent models (organotypic cultures). We will use
this system to introduce both a pdpn siRNA producing lentiviral vector (available in the lab) and
CRISPR/Cas9-mediated mutagenesis leading to significant reduction and complete loss of
PDPN expression, respectively, in the tumor cells. PDPN compromised cells will be analyzed
for i) cell proliferation, ii) (trans) migration and iii) invasion through matrigel matrix and in 3D
organotypic cultures
2. We have recently generated floxed pdpn mice, in which we already confirmed efficient deletion
of pdpn sequences via Cre recombinase technology. Crossing these mice with K14-cre mice,
applying full thickness wound healing conditions (which provoke massive expression of pdpn in
epithelial cells at the leading edge) Pdpn expression is completely abolished in vivo in
keratinocytes. In the present project, we will apply short-term TPA treatment on mouse skin
(known to strongly induce pdpn expression in basal layer keratinocytes) to evaluate the role of
Pdpn in skin hyperplasia. In addition, we will apply the DMBA/TPA protocol of chronic TPA
treatment to induce papillomas and subsequently SCC in WT and PDPN KO mice. Both tumor
incidence and tumor volume will be determined. Tumors will be harvested and characterized by
indicative immuno-histochemical analysis to define the nature of the tumor cells (particularly at
the tumor-stroma border) including their ability to execute EMT.
We will provide expertise of the chemical- induced skin carcinogenesis model to projects 3 and 9
and collaborate with both projects on transcriptional control of PDPN by the crucial SCC regulator
Wnt (project 3) and by Ripoptosome-associated cell death pathways (project 9).
5
References
1. Hummerich L, Müller R, Hess J, Kokocinski F, Hahn M, Fürstenberger G, Mauch C, Lichter P, Angel P. 2006.
Identification of novel tumour-associated genes differentially expressed in the process of squamous cell cancer
development. Oncogene 25:111-21
2. Wicki A, Christofori G. 2007. The potential role of podoplanin in tumour invasion. Br J Cancer 96:1-5.
3. Gebhardt C, Riehl A, Durchdewald M, Németh J, Fürstenberger G, Müller-Decker K, Enk A, Arnold B, Bierhaus A,
Nawroth PP, Hess J, Angel P. 2008. RAGE signaling sustains inflammation and promotes tumor development; J Exp
Med 205:275-85
4. Peterziel H, Müller J, Danner A, Barbus S, Liu HK, Radlwimmer B, Pietsch T, Lichter P, Schütz G, Hess J, Angel P.
2012 Expression of podoplanin in human astrocytic brain tumors is controlled by the PI3K-AKT-AP-1 signaling
pathway and promoter methylation. Neuro Oncol 14:426-39
5. Durchdewald M, Guinea-Viniegra J, Haag D, Riehl A, Lichter P, Hahn M, Wagner EF, Angel P*, Hess.J. 2008.
Podoplanin is a novel Fos target gene in skin carcinogenesis. Cancer Res 68:6877-83
* corresponding author
17
PACKAGE A2
4
Project Plan
4.1 Specific Aims
This project will apply a loss-of-function approach to define the function of PDPN in SCC formation
and progression in vitro and in vivo.
• apply siRNA and CRISPR/Cas9 technologies to abolish PDPN expression in SCC cell lines to
measure cell proliferation, migration and invasion
• generate mice lacking PDPN expression in keratinocytes to define the impact of pdpn
deletion on skin homeostasis, hyperplasia and tumor development and progression
Project 6: Crosstalk between melanoma cells and the blood-brain barrier: impact on
coagulation and brain metastasis to identify new anti-metastatic targets.
Prof. Dr. Stefan W. Schneider; Section of Experimental Dermatology, Dept. of Dermatology
Mannheim, Prof. Dr. Frank Winkler; Dept. of Neuro-Oncology Heidelberg; Heidelberg University
Prof. Anthony Dorling, King`s College London
Short Summary
Human malignant melanoma is a highly metastatic tumor, and especially metastatic lesions in the
brain are associated with poor prognosis. To metastasize to the brain, cancer cells must interact
with cerebral endothelial cells (ECs) and migrate through the blood-brain barrier (BBB). The
vascular endothelium is activated by tumor cells, which is followed by the release of inflammatory
cytokines and the procoagulatory protein von Willebrand factor (VWF) known to promote tumor
progression. Although treatment with heparin, a known anti-coagulant, revealed a therapeutic
effect in experimental models, the underlying mechanisms are poorly understood. To investigate
the impact of the coagulation system on tumor spreading, we will analyze the molecular pathways
of melanoma-induced EC activation using an in vitro model of the BBB, and we will address the
effect of melanoma-derived factors on EC permeability. Furthermore, taking advantage of a novel
in vivo multiphoton microscopy model allowing real-time imaging of brain metastases, we will
investigate how the coagulation pathway influences melanoma cell arrest and extravasation.
Finally, we will characterize the ret-transgenic mouse melanoma model to evaluate therapeutic
effects of anti-coagulants in vivo.
PACKAGE A2
3
State of the Art
Melanoma has the highest propensity to metastasize to the brain, and brain metastases are a
major cause of mortality. Although little is known about the interaction between melanoma cells
and brain microvascular endothelial cells (BMECs), malignant cells need to overcome the BBB to
form brain metastasis. We hypothesize that this interaction is a multimodal process that includes
melanoma cell-induced EC activation followed by the development of a proinflammatory and
procoagulatory EC surface that facilitates melanoma cell adhesion. The bidirectional melanomaEC interaction leads to an increase in BBB permeability followed by melanoma cell transmigration
and metastases formation. This hypothesis is supported by clinical and experimental reports
showing that tumor-mediated activation of the coagulation system enhances the risk of
thromboembolism and promotes tumor cell spreading in patients. Patients treated with heparins
showed a better outcome and heparins reduced the formation of metastasis in animal models.
In previous studies we could show that melanoma-derived MMP-1 activates ECs followed by the
release of proinflammatory and procoagulatory factors. Recently, we described two additional
pathways that enable melanoma cells to stimulate ECs. First, a tissue factor (TF)-thrombin-PAR1
dependent pathway was discovered. Second, we identified melanoma-derived VEGF acting via
VEGF-R2 as the main direct activator of ECs. This melanoma-induced EC activation was
attenuated by heparins. All these pathways induce an acute Weibel-Palade body (WPB) exocytosis
and the formation of ultralarge VWF fibers at the luminal surface of ECs, directly mediating platelet
adhesion. Moreover, we could show that VWF supports leucocyte extravasation by increasing
endothelial permeability, a process that may exhibit similarities with tumor cell extravasation.
Moreover, our data show that melanoma cell-induced EC activation depends on the type of
melanoma cells and ECs. However, studies on the molecular mechanisms of melanoma cell
interaction with the endothelium of the BBB are lacking. The Winkler lab has established novel
applications of in vivo multiphoton microscopy (MPLSM), where brain endothelial cells, blood
perfusion, single cancer cells in subcellular resolution, and the single steps of brain metastasis
formation of melanoma cells can be imaged through a cranial window in real time over months.
Application of this technology allows the study the interaction of melanoma cells with brain ECs in
18
the physiological microenvironment. This unique experimental platform is available to other
projects of this proposal to investigate the role of molecular pathways and the effect of therapeutic
intervention on distinct steps of the metastatic cascade. All in all, new mechanistic insights into the
crosstalk between melanoma and BMECs may have important consequences for diagnostic and
therapeutic strategies in patients suffering from malignant melanoma.
4
Project Plan
4.1 Specific Aims
1. Impact of coagulation on tumor spreading
2. Mechanisms of melanoma - blood-brain barrier interaction
3. Impact of anticoagulants on brain metastasis in an animal model
Cell-based assays and in-vivo stemness reporter systems to identify the role of melanoma stem
cells will be performed with Projects 1 and 2. Angiopoetin-2 and its impact on BBB permeability will
be analyzed with Project 8. Analysis of brain metastases in the ret mouse model will be
characterized together with Project 13.
5
1.
2.
3.
4.
5.
References
Desch A, Strozyk EA, Bauer AT, Huck V, Niemeyer V, Wieland T, Schneider SW. 2012. Highly Invasive Melanoma
Cells Activate the Vascular Endothelium via an MMP-2/Integrin alphavbeta5-Induced Secretion of VEGF-A. Am J
Pathol 181:693-705.
Kerk N, Strozyk EA, Poppelmann B, Schneider SW. 2010. The mechanism of melanoma-associated thrombin
activity and von Willebrand factor release from endothelial cells. J Invest Dermatol 130:2259-2268.
Schneider SW, Nuschele S, Wixforth A, Gorzelanny C, Alexander-Katz A, Netz RR, Schneider MF. 2007. Shearinduced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci USA 104:7899-7903.
Pappelbaum KI, Gorzelanny C, Grässle S, Suckau J. Laschke MW, Bischoff M, Bauer C, Schorpp-Kistner M,
Weidenmaier C, Schneppenheim R, Obser T, Sinha B, Schneider SW. 2013. Ultra-large von Willebrand factor
fibers mediate luminal Staphylococcus aureus adhesion to an intact endothelial cell layer under shear stress.
Circulation 128:50-59.
Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WE, Goldbrunner R, Herms J, Winkler F. 2010. Real-time
imaging reveals the single steps of brain metastasis formation. Nat Med 16:116-122.
19
PACKAGE A2
1. The molecular mechanisms of melanoma-mediated activation of BMECs in vitro and on the
integrity of the EC monolayer will be analyzed. In previous work we have found that some
melanoma cell lines such as A2058 can form parenchymal brain metastases, whereas other
lines (i.e. B16F10) do not. The metastatic potential is reflected by a distinct ability of EC
activation. In order to clarify the molecular mechanisms of melanoma-derived mediators that
activate ECs, different melanoma cell lines will be compared by gene expression analysis and
proteome profiling.
2. a) The impact of melanoma-mediated EC activation on expression of adhesion molecules and
melanoma cell adhesion will be assessed using microfluidic devices established by the
Schneider lab. b) In vivo MPLSM imaging of VWF and adhesion molecules, and their colocalization with arrest and extravasation of melanoma cells in the brain will be investigated.
3. Finally, we will study the relevance of our results using the ret-transgenic mouse melanoma
model. To this end, VWF-selective changes in BBB integrity will be evaluated by analysis of
candidate molecules for vascular permeability, by application of heparins, new anticoagulants
and knockdown of adhesion factors in melanoma cells in our in vivo MPLSM imaging model.
We will thereby determine their role in the metastatic cascade, which should lead to rapid
identification of most promising therapeutic targets.
Project 7: Liver-specific endothelial mechanisms of melanoma metastasis
PD Dr. Cyrill Géraud, Prof. Dr. Sergij Goerdt, Dept. of Dermatology, Medical Faculty
Mannheim, Heidelberg University
Dr. Ilaria Malanchi, Tumor Host Interaction Group, London Research Institute, Cancer Research
UK, London
Short Summary
Hematogenous metastasis is remarkably organ-specific. The liver with its unique sinusoidal
vascular system is one of the preferred sites of malignant melanoma (MM) metastasis. Liverspecific, endothelial-dependent mechanisms of MM cell dissemination will be analyzed by
scrutinizing liver sinusoidal endothelial cell (LSEC)-specific candidate molecules such as Stabilin-1
and Stabilin-2 identified by us as well as other scavenger and lectin-like receptors. Their role in
tumor cell adhesion and transmigration will be investigated in a microfluidic chamber model in vitro
using over-expression in human umbilical vein endothelial cells (HUVEC) as well as by using
LSEC from the respective KO animals. A special focus will be on hyaluronan (HA)-mediated
interactions. Results will be confirmed in vivo using the ret model as well as a B16 luciferase model
of MM metastasis to the liver in WT and KO animals. The final goal of this project is to develop
novel strategies to treat metastasis in this devastating disease.
PACKAGE A2
3
State of the Art
Metastatic spread to distant organs in general comprises a series of steps in which endothelial
cells (EC) are intricately involved such as tumor cell adhesion and transmigration. In many
cancers, including MM, however, cancer cell dissemination is remarkably organ-specific. Organspecific metastasis is likely caused by tumor cell heterogeneity as well as by organ-specific stromal
factors. Among these, EC heterogeneity may impact on tumor-EC interactions by modulating the
well-known general adhesive mechanisms or by providing organ-specific pathways. Besides the
lungs and the brain, the liver is a preferred site for distant metastasis in MM, and the primary site
for metastasis in uveal melanoma. LSEC are a prime example of organ-specific EC differentiation.
LSEC selectively express several scavenger and lectin-like receptors such as stabilin-1/2, LYVE-1,
MRC1, CD32B, CLEC-1B, -4G, and -4M. Two of these molecules, stabilin-2 and LYVE-1 are
known HA receptors. In addition, the HA receptor CD44 is also expressed by LSEC. Furthermore,
HA-dependent mechanisms have been shown to be of high importance for melanoma metastasis
in general and especially in the liver. HA is generated by HA synthases on the surface of MM cells
and could contribute to liver metastasis by binding to stabilin-2, LYVE-1 or to CD44. Conversely,
CD44 has also been found on many types of tumor cells including MM. Therefore, MM cells could
also adhere to HA bound by the three HA receptors on the surface of LSEC. In addition, stabilin-1
and Clec-4G/LSECtin have already been demonstrated to mediate binding of tumor cells other
than MM cells to LSEC. In summary, the analysis of this set of candidate LSEC adhesion
molecules may open new avenues to target EC-dependent, organ-specific MM metastasis to the
liver.
Our group has a longstanding track record in analyzing the specific molecular repertoire and
functions of LSEC including identification of the scavenger receptors stabilin-1 and -2. Stabilin-2
KO mice, although displaying no obvious phenotype, show highly increased plasma levels of HA
proving that stabilin-2 is the major receptor for HA turnover. Due to impaired clearance of other
noxious blood factors, stabilin-1/2-/- double deficient mice have a reduced lifespan and develop
severe glomerulosclerosis indicating the importance of stabilin function for the whole organism.
LSEC specifically produce wnt2 that acts as an autocrine growth factor by cross-stimulating the
VEGF pathway. Comprehensive gene expression analysis revealed a LSEC-specific, hepatic
microenvironment-dependent differentiation program comprising distinct sets of growth and
transcription factors as well as of adhesion- and endocytosis-associated molecules including the
novel junctional protein Leda-1.
20
4
Project Plan
4.1 Specific Aims
The general aim of the project is to analyze the organ-specific, endothelial-dependent mechanisms
of MM cell dissemination to the liver. For this purpose, we will thoroughly study MM-LSEC
interactions in vitro and in vivo. In vitro, we will analyze (1) MM cell-LSEC adhesion and
transmigration in a microfluidic chamber model using HUVEC retrovirally transfected with LSECspecific candidate adhesion molecules, as well as LSEC isolated from the respective knockout
mice. Special attention will be given to HA-mediated mechanisms. In vivo, (2) LSEC-dependent
MM metastasis to the liver will be investigated using a B16 luciferase model, the ret MM model,
and a human xenotransplant model of MM metastasis.
Experimental program
1. LSEC-specific candidate molecules for liver-specific melanoma-EC adhesion and
transmigration, i.e. stab1, stab2, Lyve-1, MRC1, CD32b, CLEC-1B, -4G, and -4M, will be
retrovirally transfected into HUVEC. Using transwell migration assays and a microfluidic
chamber device that simulates organ-specific flow conditions, MM cell adhesion and
transmigration will be studied using transfected HUVEC as well as murine LSEC and – as a
control – murine lung microvascular endothelial cells (LMEC) from wild-type and knock out
animals (stab1-/-, stab2-/-, Lyve-1-/-, CD44-/-). In these assays, the relevance of HAdependent mechanisms will be analysed by pre-incubation of either MM or endothelial cells
with HA to block HA binding proteins, by hyaluronidase treatment and by inhibition of HA
synthases. The function of CD44 expressed by MM cells as a ligand for HA deposited on LSEC
will be investigated by CD44 knock-down in MM cells.
2. In vivo, organ-specific MM cell-EC adhesion and metastasis will be analysed by injecting
luciferase-expressing B16F10 mouse MM cells into the spleen (liver metastasis) or tail vein
(lung metastasis) of wild-type and knockout animals (stab1-/-, stab2-/-, Lyve-1-/-, CD44-/-). HA
dependent mechanisms will be studied in vivo using i.p. injection of hyaluronidase and p.o.
administration of HA synthase inhibitors. Development of metastases will be traced and
quantified by bioluminescence in vivo imaging. Adhesion molecule-deficient animals will be
back-crossed with ret MM mice and analysed for spontaneous liver metastases. Adhesion
molecules that can be shown to be involved in MM adhesion and metastasis in those murine
models will be further scrutinized in a xeno-transplant model of human melanoma metastasis.
Melanoma cell-LSEC adhesion will be analyzed with Project 6 (microfluidic chamber) and Project 1
(CD44-mediated adhesion). The ret model of MM and the human MM mouse xeno-transplant
model will be provided by Projects 13 and 12, respectively.
5
1.
2.
3.
References
Schledzewski K*, Geraud C*, Arnold B, Wang S, Grone HJ, Kempf T, Wollert KC, Straub BK, Schirmacher P,
Demory A, Schonhaber H, Gratchev A, Dietz L, Thierse HJ, Kzhyshkowska J, Goerdt S. 2011. Deficiency of liver
sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic
clearance of noxious blood factors. J Clin Invest 121:703-14.
Geraud C*, Schledzewski K*, Demory A, Klein D, Kaus M, Peyre F, Sticht C, Evdokimov K, Lu S, Schmieder A,
Goerdt S. 2010. Liver sinusoidal endothelium: a microenvironment-dependent differentiation program in rat including
the novel junctional protein liver endothelial differentiation-associated protein-1. Hepatology 52:313-26.
Klein D, Demory A, Peyre F, Kroll J, Augustin HG, Helfrich W, Kzhyshkowska J, Schledzewski K, Arnold B, Goerdt
S. 2008. Wnt2 acts as a cell type-specific, autocrine growth factor in rat hepatic sinusoidal endothelial cells crossstimulating the VEGF pathway. Hepatology 47:1018-31.
21
PACKAGE A2
4.2
Research Area B – Primary Resistance to Cell Death and Immunity
Project Package B1: Primary Resistance to Cell Death (Projects 8-10)
Project 8: Does Angiopoietin-2 protect malignant melanoma tumor cells from
anoikis?
Dr. Moritz Felcht, Dept. Dermatology, Med. Faculty Mannheim, Heidelberg University;
Prof. Dr. Hellmut G. Augustin, Vascular Biology & Tumor Angiogenesis, Med. Faculty
Mannheim, Heidelberg University, and German Cancer Research Center, Heidelberg
Prof. Kairbaan Hodivala-Dilke, Centre for Tumor Biology, Barts Cancer Institute, Barts and The
London, Queen Mary University College of London
Short Summary
Increased levels of the Tie2 ligand Angiopoietin-2 (Ang-2) can be detected in the blood from
patients suffering from metastasized malignant melanoma (MM) (AJCC III/ IV). Furthermore,
different studies could show that Ang-2 is essential for primary MM tumor growth and metastasis
formation in mice. Ang-2 is mainly secreted by activated endothelial cells but can also be produced
by MM tumor cells themselves. Therefore, Ang-2 may act in an autocrine as well as in a paracrine
manner on MM tumor cells. In the absence of its high affinity receptor Tie2, Ang-2 directly
associates with and signals through integrins. Integrin activation is required during metastasis
formation to protect tumor cells from anoikis, apoptosis induced by inadequate cell-matrix
connection. Preliminary data by the applicants show that Tie2 negative MM tumor cells are
protected from anoikis by exogenous Ang-2 stimulation. Consequently, this project aims to study if
anoikis resistance mediated by Ang-2 represents an essential new pathomechanism during MM
metastasis formation and if this can be used therapeutically.
PACKAGE B1
3
State of the Art
3.1 State of knowledge in the field: Angiopoietin-2 (Ang-2) is essential during MM metastasis
formation and increased levels of Ang-2 can be detected when metastases have been formed.
Metastasis formation passes through the single steps invasion, intravasation, intravascular
survival, extravasation and colony formation. Intravascular survival of tumor cells requires
protection from anoikis, apoptosis induced by inadequate cell-matrix connection. Protection from
anoikis is classically acquired by integrin activation [3] but may also be achieved by receptor
activation. Recently, the applicants could show that integrins may also be activated by Ang-2 in the
absence of Tie2 receptor. Ang-2 can be detected in some Tie2 negative malignant melanoma cell
and may therefore directly bind to and activate integrins. Yet, the impact of Ang-2 stimulation of
MM cells has not been studied.
3.2 Previous work by the participants: In the presence of Tie2, Ang-2 induces complex
formation of Tie2-FAK-αvβ3 integrin, FAK phosphorylation at Ser910 but not at Tyrosine397,
induces αvβ3 integrin internalization/ degradation and endothelial destabilization (Thomas*,
Felcht*, et al, 2010). In the absence of Tie2 receptor Ang-2 binds αvβ3, αvβ5 and α5β1 integrins
and induces FAK phosphorylation at Tyrosine397 and RAC activation (Felcht et al., 2012). The
binding of Ang-2 to integrins is tightly regulated and obligates absence of the high affinity receptor
Tie2, an acid environment and integrin expression in their active conformation (Felcht et al., 2012).
Functionally, Ang-2 induces in endothelial cells migration and sprouting independent of Tie2
expression (Felcht et al., 2012). In A375 MM tumor cells Ang-2 stimulation protects from anoikis in
vitro (unpublished). A375 cells express αvβ3 integrin but not Tie2 receptor or αvβ5 (unpublished).
Tumor specimens of metastatic MM show CD34 negative/ αvβ5 expressing and/or αvβ3
expressing cells (unpublished).
4
Project Plan
4.1 Specific Aims
I. Which requirements are needed for Ang-2 protection from anoikis?
II. Is there a therapeutic relevance of Ang-2 induced protection from anoikis?
22
Primary cutaneous MM cells will be generated in collaboration with project 2. Vascular
remodelling/pruning is studied in collaboration with project 3. The studies of molecular signalling of
apoptosis will be supported by project 9 and 10. The ret transgenic melanoma mouse model will be
provided by project 13.
5
1.
2.
3.
4.
5.
References
Felcht M, Luck R, Schering A, Seidel P, Srivastava K, Hu J, Bartol A, Kienast Y, Vettel C, Loos EK, Kutschera S,
Bartels S, Appak S, Besemfelder E, Terhardt D, Chavakis E, Wieland T, Klein C, Thomas M, Uemura A, Goerdt S,
Augustin HG. 2012. Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin
Invest 122:1991-2005.
Thomas M*, Felcht M*, Kruse K, Kretschmer S, Deppermann C, Benest AV, Fiedler U, Augustin HG. 2010.
Angiopoietin-2 stimulation of endothelial cells induces alphavbeta3 integrin internalization and degradation. J Biol
Chem 285:23842-9. *equal contribution
Augustin HG, Koh GY, Thurston G, Alitalo K. 2009. Control of vascular morphogenesis and homeostasis through
the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165-177.
Helfrich I, Edler L, Sucker A, Thomas M, Christian S, Schadendorf D, Augustin HG. 2009. Angiopoietin-2 levels are
associated with disease progression in metastatic malignant melanoma. Clin Cancer Res 15:1384-92.
Nasarre P, Thomas M, Kruse K, Helfrich I, Wolter V, Deppermann C, Schadendorf D, Thurston G, Fiedler U,
Augustin HG. 2009. Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation
but is dispensable for later stages of tumor growth. Cancer Res 69:1324-33.
23
PACKAGE B1
(I.A.) Various MM tumor cells
(C32, SK-Mel-28, RPMI 7951,
HAT 144, SK-Mel2, WM9,
WM35, MV3, CRL 1676,
Malme 3M, MeWo, WM 1158) will be compared for their
Ang-2
induced
anoikis
resistance in different anoikis
assays. These studies will
include primary MM cells as
well as Ang-2 studies in the
ret
transgenic
melanoma
mouse model. PCR/ELISA
studies will compare Ang-2 levels. (I.B.) Integrin expression of the MM cells (see I.A.) will be
compared by PCR, Western Blot, IP and FACS analyses i. Inhibition studies (antibodies, siRNA,
shRNA) should unravel the relevance for anoikis resistance. (I.C.) Tie2 expression will be studied
in the different MM cells (see I.A.) (PCR/Western blot). Inhibitory (siRNA,
antibodies)/overexpression (shRNA) studies will be compared with the integrin expression/anoikis
sensitivity. (I.D.) Intra- and extracellular Ang-2 signalling has been observed. MM cells with low,
intermediate & high levels of Ang-2 (see I.A.) will be analysed in inhibition studies (siRNA, shRNA,
antibody) in the anoikis assay. Exogenous (recombinant, conditional media w. adenoviral
overexpression [Ad-Ang-2])) vs. endogenous (Ad-Ang-2) Ang-2 stimulation will support the
analyses. (I.E.) AKT, ERK, mTOR, JNK, Mcl-1 and bad signalling will be analysed.
Intrinsic/extrinsic apoptosis will be studied in collaboration with project 9. Pharmacological
inhibitory studies (Worthmanin, UO126, Rapamycin, zVAD-fmk) will be performed in parallel. (I.F.)
MM cells (different integrin/Ang-2/ Tie2 expression profiles) will be used for metastasis studies in
vivo. Metastasis formation will be studied by conventional microscopy and correlated with anoikis
sensitivity. Control experiments with Ang-2 overexpression and inhibition (antibodies) will support
the in vivo study. Inhibition experiments (antibodies) within the ret transgenic melanoma mouse
model will finalize the in vivo studies. (II.A.) Preliminary studies detected αvβ3 integrin in nonvascular MM areas in tumor specimens from patients. Integrin expression studies (see I.B.) will be
performed in a larger cohort with co-staining against melanocytic markers. (II.B.) The signalling
studies (see I.e.) will be followed by combination inhibitory studies in vitro.
Project 9: The regulation of Ripoptosome-associated cell death pathways in
keratinocyte skin cancer
Prof. Dr. Martin Leverkus, Section of Molecular Dermatology, Department of Dermatology;
Medical Faculty Mannheim, Heidelberg University
Prof. Pascal Meier, ICR, Head of Apoptosis Team, The Break-through Toby Robins Breast
Cancer Research Centre, Institute of Cancer Research, London
Short Summary
For progression and metastasis of SCC, the crosstalk of transformed keratinocytes with tumor
stroma and immune cells is of importance. Cell death resistance is a prerequisite for progression
and metastasis. We recently showed that the Ripoptosome – an intracellular signalling platform
containing RIP1, Caspase 8, FADD, and cFLIP - controls apoptosis and necroptosis in SCC. The
Ripoptosome is necessary for signaling initiated by membrane-bound receptors (death receptors,
TLR 3) and thus shapes the quality not only of cell death but also of the immune response
potentially activated by necroptosis. The project will investigate the structure, function, and
assembly of the Ripoptosome in different progression stages of primary and transformed
keratinocytes and SCC in vitro and in vivo. We will use in vitro model systems (HaCaT tumor
progression model) and representative tumor cell lines in vitro. Functional studies will make use of
lentiviral knockdown or overexpression of constituents of the Ripoptosome depending on their
expression. Our project promotes understanding of the function of different components of the
Ripoptosome for tumor progression and metastasis of SCC.
PACKAGE B1
3
State of the Art
The major problem of SCC is its multiplicity, whereas metastasis only occurs in locally progressed
stages. The reason for this relative resistance to metastasis is currently unclear but may involve
immune surveillance by the host activated by inflammatory signals. Cellular death and
inflammatory pathways in SCC are regulated by membrane bound receptors that can activate
caspases in a pro-apoptotic or inflammatory manner. Activation of cell death via TLR7 by its ligand
imiquimod is sufficient for elimination of a high proportion of in situ carcinoma by TRAIL-dependent
cell death. Cell death activation can occur via the so-called Death Inducing Signaling Complex
(DISC) for death receptors (DR). Alternatively cell death is initiated by recruitment of adaptor
molecules such as TRIF or MyD88 to TLR3 or other TLRs. Most of these signaling platforms
mediate apoptosis via FADD and caspase 8, whereas more recently the role of the RIP1-RIP3
module (necrosome) for receptor-induced necroptosis has been demonstrated. The decision for
the outcome of receptor activation is dependent on the regulation of the components and activity
within the Ripoptosome, a recently described novel intracellular signaling platform. The inhibitor of
apoptosis proteins (IAPs) such as cIAP1/2 and XIAP were shown to suppress the formation of
some of these signaling platforms, in particular the Ripoptosome. The importance of the
Ripoptosome for receptor-induced cell death responses in different progression stages of SCC is
unknown to date and will be investigated in this project.
In our preliminary work we have studied the formation of the molecular complex that we named the
Ripoptosome, which consists of FADD, RIP1, caspase 8 and cFLIP. Our studies were performed in
HaCaT and in advanced tumor progression forms derived from HaCaT. By studying these cellular
models we could demonstrate the decisive role of RIP1 for the formation of the Ripoptosome, and
a crucial role of the RIP1 kinase activity for necroptosis execution induced by death receptors or
TLR3 ligands. Furthermore, we could identify the critical role of cFLIP in promoting cell death
resistance of A5RT3 (the metastatic cell line of the HaCaT tumor progression model) to cell death
mediated by the Ripoptosome. We will therefore aim to further study assembly, activation, and
execution of cell death by the Ripoptosome, a complex known to mediate both apoptosis and
24
necroptosis. Ultimately we will aim to investigate if modulation of this complex can be exploited as
a novel target for tumor therapy of early or late SCC of the skin.
1. First we will analyze the differences in expression of key complex components (FADD, RIP1,
RIP3, initiator caspases 8 and 10, Mixed lineage kinase domain-like (MLKL)) in various cell
lines at the mRNA (qPCR) and protein levels (Western blotting). To this end we will use a
number of model cell lines (HaCaT and MET SCC progression models) as well as primary
keratinocytes and SCC cells and compare results with data derived from ex vivo analysis of
human tumors (immunohistochemistry, qPCR, Western blotting). These studies will help to
define the main differences between primary keratinocytes and SCC cells.
2. The next step will be the functional analysis of cell death in the above-mentioned primary cells
and cell lines. We will analyze the caspase- and RIP1 kinase-dependency of cell death in
response to a number of stimuli (TLR or death ligands) by using inhibitors (zVAD-fmk,
Necrostatin-1, necrosulfonamide). The morphology of cell death will be determined with
combinations of Hoechst and SYTOX Green staining in a kinetic manner using fluorescent
microscopy. Caspase-dependent cell death will be monitored by initiator/effector caspase
cleavage. Using reverse transfection, transient siRNA transfection against RIP3, MLKL, or
caspase-8 will be utilized to dissect which signalling pathways are required for cell death
execution.
3. We will then study Ripoptosome formation and activity in selected cell lines (primary and lines
derived from SCC progression models) using caspase-8 coimmunoprecipitation. Finally we
want to analyze SCC cell lines that show primary resistance to cell death stimuli. We will
investigate which Ripoptosome components are critical for cell death resistance, and if proteins
such as RIP1, RIP3, MLKL, or others can reconstitute or block the ability of cells to undergo
Ripoptosome-induced cell death using retro/lentiviral knockdown of these key components. For
selected questions we will extend these studies to organotypic model systems to investigate if
identified genes shape a differential cell death response in a three-dimensional environment.
Our project will utilize nude mouse model systems (Project 2) and skin carcinogenesis models
(Project 5) to extend the in vitro findings in vivo. Genetic manipulation to eliminate Ripoptosomeassociated genes in SCC cell lines via CRISPR/Cas9 will be done in collaboration with project 3
and 4.
5. References
1. Panayotova-Dimitrova D, Feoktistova M, Ploesser M, Kellert B, Hupe M, Horn S, Makarov R, Jensen F, Porubsky S,
Schmieder A, Zenclussen AC, Marx A, Kerstan A, Geserick P, He YW, Leverkus M. 2013. cFLIP regulates skin
homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep 5:397-408.
2. Cullen SP, Henry CM, Kearney CJ, Logue SE, Feoktistova M, Tynan GA, Lavelle EC, Leverkus M, Martin SJ. 2013.
Fas/CD95-Induced Chemokines Can Serve as "Find-Me" Signals for Apoptotic Cells. Mol Cell 17:1034-1048
3. Feoktistova M, Geserick P, Kellert B., Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Hacker G,
Leverkus M. 2011. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death
complex differentially regulated by cFLIP isoforms. Mol Cell 43:449-463.
4. Geserick P, Hupe M, Moulin M, Wong WW, Feoktistova M, Kellert B, Gollnick H, Silke J, Leverkus M. 2009. Cellular
IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment. J Cell Biol 187:1037-1054.
5. Kavuri SM, Geserick P, Berg D, Dimitrova DP, Feoktistova M, Siegmund D, Gollnick H, Neumann M, Wajant H,
Leverkus M. 2011. Cellular FLICE-inhibitory protein (cFLIP) isoforms block CD95 or TRAIL-induced NF-kB activation
independent of caspase-8 cleavage. J Biol Chem 286:16631-16646.
25
PACKAGE B1
4
Project Plan
4.1 Specific Aims
1. Compare expression of the key Ripoptosome components in SCC tumor progression models in
vitro, primary keratinocytes and SCC cell lines and primary tumor samples to identify
differential expression.
2. Investigate the qualitative and quantitative cell death responses in SCC tumor progression
models and compare it to primary human keratinocytes.
3. Compare Ripoptosome formation and activity in selected cell lines and investigate the
functional relevance of its components by knockdown or overexpression studies.
Project 10: IAP antagonists: A novel therapeutic option to overcome cell death
resistance in malignant melanoma?
Dr. Peter Geserick, Prof. Dr. Martin Leverkus, Dept. of Dermatology, Medical Faculty
Mannheim, Heidelberg University
Prof. Henning Walczak, Cell Death and Inflammation Laboratory, Cancer Institute, University
College London
Short Summary
Acquisition of cell death resistance is a critical step during skin tumorigenesis. Inhibitor of
apoptosis proteins (IAPs) are negative regulators of caspase-dependent apoptotic (e.g. X-linked
IAP) and receptor interacting protein 1 (RIP1)-dependent necroptotic (e.g. cIAPs) cell death
induced by death receptors. The caspase-8 inhibitor cFLIP is upregulated during tumor
progression in malignant melanoma, and protects tumor cells from receptor-mediated cell death.
Notably, the short isoform of cFLIP (cFLIPS) protects cells from apoptotic but not necroptotic cell
death. This project will study how different IAPs regulate the diverse forms of cell death in
malignant melanoma. Therefore, we will investigate (1) how cIAPs regulate the quality and quantity
of cell death in cultured malignant melanoma cells; (2) the function of different components of
intracellular death pathways and the impact of cFLIP isoform expression on apoptotic and
necroptotic cell death and; (3) the potential of IAP antagonists for tumor suppression in xenograft
mouse models. These studies will functionally validate the role of cFLIP isoforms in conferring
resistance to different forms of cell death, and will elucidate how this relates to the overall
therapeutic response in malignant melanoma.
PACKAGE B1
3
State of the Art
Activation of death receptor (DR)-induced apoptosis transmitted by cytokines such as TRAIL and
CD95L is a required mechanism for elimination of unwanted and transformed cells. This process is
highly controlled by antiapoptotic proteins that control caspase activity initiated either by DRs
(cFLIP inhibits Caspase 8) or intracellularly (e.g. XIAP blocks caspase-9 and 3). In contrast, cIAPs
inhibit necroptosis by regulation of a RIP1-controlled signalling platform. Suppression of such cell
death responses mediated by upregulation of cell death inhibitory proteins during tumor
progression may confer therapeutic resistance in malignant melanoma. Melanoma cells are known
to be highly resistant against death ligand-mediated cell death. Inhibition of this cell death
resistance by combined activation of DRs and suppression of IAP activity using the respective
antagonists could represent a promising novel anti-cancer strategy for malignant melanoma. IAP
antagonists suppress the caspase-inhibitory function of XIAP and additionally promote rapid
degradation of cIAP1 and 2. The
consequences of these activities of
IAP antagonists are either increased
apoptosis induction by effector caspase-3
activity, or promotion of apoptosis or
necroptosis initiated by activation of the
RIP1/RIP3 signalling machinery. These
interesting molecular processes could be
of critical relevance to overcome cell
death resistances in melanomas and
therefore for tumor suppression.
Over the past years our group intensively worked on the identification of resistance mechanisms in
skin tumors. We identified the critical role of cFLIP for DR-induced cell death in melanoma and the
role of IAPs for regulation of necroptotic cell death responses. We further demonstrate necroptosis
induction in transformed, but not primary cells when IAP function is suppressed. Analysis of these
26
signalling pathways in melanoma cells demonstrated a substantial upregulation of cFLIP and IAPs,
and concomitant increased resistance to death ligand-mediated cell death in malignant melanoma
cells. Intriguingly, in the presence of IAP antagonists, we were able to overcome cell death
resistance and increase sensitivity to TRAIL, indicative of the indispensable role of IAPs for cell
death resistance in melanoma cells. A more precise role of cFLIP in the regulation of DR-induced
cell death was shown by cFLIP overexpression. In line with our previous studies, both cFLIP
isoforms were able to block TRAIL-induced apoptosis in melanoma. However, only cFLIPs
promotes necroptotic cell death responses in the presence of IAP antagonists (Figure 1). These
data are indicative of the critical but differential role of cFLIP isoforms in cell death regulation.
A repertoire of melanoma cells representing different tumour progression stages will be analysed
for expression of cFLIP and IAP proteins (XIAP, cIAP1/2) as well as of their counteracting protein
molecules (caspases, RIP1/RIP3, MLKL) using various biochemical approaches (immunoblot,
qPCR). The determination of the quality and quantity of cell death initiated by treatment with TRAIL
or CD95L will be analyzed using crystal violet and PI/AnnexinV assay, and fluorescence
microscopy. The relevance of the respective proteins (cFLIP, IAPs) involved in cell death
resistance in melanomas will be investigated by genetic manipulation of the endogenous
expression levels (siRNA, lentiviral shRNA, retroviral expression of cFLIP) followed by analysis of
the quality and quantity of cell death upon combined IAP antagonist and DL treatment. To
investigate the role of cFLIPs and IAPs for tumor growth and cell death resistance, appropriate
established and biochemically- characterized melanoma cells will be xenotransplanted into
immune deficient mice. Tumor growth and metastasis as well as the effect of IAP antagonists in
combination with DL (TRAIL, CD95L) for cell death sensitivity and for tumor suppression will be
investigated in mice with established melanoma in vivo following DL and IAP antagonist treatment.
Cooperation with project 4 will allow us to perform optimal knockdown conditions in large-scale but
also in small scale for specific proteins (cFLIP, IAPs) in melanoma. Cooperation with project 2 will
enable us to perform experiments with xenograft mouse models. We will share our expertise in the
field of cell death signalling in vitro and in vivo with projects 3, 5, 8, and 11.
5
1.
2.
3.
References
Feoktistova M*, Geserick P*, Kellert B, Panayotova-Dimitrova D, Langlais C, Hupe M, Cain K, MacFarlain M,
Häcker G, Leverkus M. 2011. cIAPs block Ripoptosome formation, a RIP1/caspase 8 containing intracellular cell
death complex differentially regulated by cFLIP isoforms. Mol Cell 43:449-63 (* equal contribution)
Geserick P, Hupe M, Moulin M, Wong WW, Feoktistova M, Kellert B, Gollnick H, Silke J, M Leverkus. 2009.
Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment. J Cell Biol. 187:10371054.
Geserick P, Drewniok C, Hupe M, Haas TL, Diessenbacher P, Sprick MR, Schon MP, Henkler F, Gollnick H,
Walczak H, Leverkus M. 2008. Suppression of cFLIP is sufficient to sensitize human melanoma cells to TRAIL or
CD95L-mediated apoptosis. Oncogene 27:3211-3220.
27
PACKAGE B1
4
Project Plan
4.1 Specific Aims
The general aim of the project is to study the mechanistic relevance of IAPs and cFLIPs for
resistance of DR-induced cell death in melanoma cells and the role of IAP antagonists as a
potential therapeutic for melanoma treatment. For this purpose, we will analyze expression of IAPs
and cFLIP isoforms and check the sensitivity of cells to TRAIL in the presence or absence of IAP
antagonists from in a set of melanomas representing different tumour stages, and in melanoma
genetically modified with downregulation or overexpression of IAPs and cFLIPs. The growth and
metastasis of melanomas expressing cFLIP isoforms upon xenotransplantation into immune
deficient nude mice will be assessed. Finally, the ability of a combination therapy of IAP
antagonist/DL to treat established tumors in a xenograft mouse model will be analyzed.
Research Area B – Primary Resistance to Cell Death and Immunity
Project Package B2: Primary Resistance to Tumor Immunity (Projects 11-13)
Project 11: Characterization and modulation of CC-chemokine receptor 6 (CCR6) mediated immunosurveillance in malignant melanoma
Dr. Anke S. Lonsdorf, Prof. Dr. Alexander H. Enk, Department of Dermatology; Medical
Faculty Heidelberg, Ruprecht-Karls-University Heidelberg
Prof. Fran Balkwill, Centre for Cancer and Inflammation, Barts Cancer Institute, London
Short Summary
The general objective of this research proposal is to evaluate the distinct functional contribution of
CC-chemokine receptor (CCR) 6 interactions with its cognate ligand CCL20 in modulating specific
cellular anti-melanoma immune responses. The relevance of the CCR6/CCL20 axis for the
immune control of melanoma at the primary tumor site and the skin draining lymph nodes (LNs) will
be studied in two established murine models: 1) the B16 transplanted melanoma model in C57BL/6
(WT) and CCR6 knockout (KO) mice and 2) the spontaneous melanoma model in Ret-transgenic
mice as well as human melanoma tissue samples. An increased understanding of the functional
interplay between CCR6/CCL20-guided pathways in the local control of melanoma and draining
LNs may allow for the identification of novel therapeutic strategies on a molecular level.
PACKAGE B2
3
State of the Art
Chemokines, a family of small, secreted molecules, and their cognate G-protein-coupled receptors
play an essential role in the elicitation of specific immune responses, particularily directed
compartment-specific migration of immune and tumor cells (i.e. chemotaxis). CCL20 and the antimicrobial peptide ß-defensin expressed in the epidermis are a potent impetus for the recruitment of
subsets of dendritic cell (DC), B-cells and memory T cell subsets expressing CCR6, its exclusive
receptor. In addition to its constitutive expression the epidermis, CCL20 and a CCR6- expressing
immune cell infiltrate has been detected in several malignancies, including melanoma. Yet, the
functional contribution of the CCR6/CCL20 axis in the immune control of melanoma remains
controversial: While CCR6/ CCL20 interactions have been found to support anti-melanoma
immune responses in a murine model of lung metastasis, tumor-derived CCL20 has been reported
to promote tumor growth and immune escape; partially by recruiting subsets of tolerogenic
immature DC or regulatory T cells. Analysis of the kinetics and distribution of CCR6-guided
immune cell subsets and their functional contribution for the immune control of melanoma
comprises the focus of this research proposal. Furthermore, stimuli by which the expression of
CCR6 ligands may be modulated at the tumor site and/ or the skin-draining LN are poorly
understood and their potential relevance for anti-tumoral immune responses warrants further
investigation.
Our group has a long-standing interest in studying mechanisms of compartment-specific trafficking
of melanoma and immune cells with a particular focus on the role of chemokine interactions. In
previous studies we provided evidence that CCR6 expression on DC subsets and effector T cells
vitally contributes to the elicitation of skin modulating immune responses by directing their
recruitment to sites of enhanced CCL20 expression (Hedrick and Lonsdorf et al., 2009). We have
also demonstrated that small-molecule activators, such as toll-like receptor (TLR)-activating
microbial products, support the formation of protective antitumoral immune responses in the skin
(Lonsdorf et al., 2003) and that the accumulation of both, epidermal chemokines and CCR-bearing
immune cells in skin-draining LNs may be amplified by topically applied immunmodulators in vivo
(Chien et al., 2009; Huang et al., 2008).
28
1. A) Luciferase-transduced murine B16 melanoma (B16-luc) will be injected s.c. into syngeneic
WT and CCR6 KO mice. Kinetics of skin tumors and LN metastases will be monitored in vivo
(calliper, bioluminescence analysis). Additionally, tumor burden and melanoma metastasis will
be quantified ex vivo by exploiting a bioluminescence reporter system. .Immune cell infiltrates,
tumor vascularisation and the predominant chemokine/CCR and cytokine profiles will be
analysed (immunohistochemistry (IHC), FACS, RT-PCR) in primary transplanted B16-luc
melanomas and corresponding skin-draining LNs. Results will be validated in spontaneously
arising melanomas in Ret-transgenic mice B) Subsets of CCR6-expressing immune cells from
tumor-bearing WT mice will be adoptively transferred into CCR6 KO mice before/ after B16-luc
inoculation. Tumor kinetics and LN metastasis, tumor-homing capabilities and alterations in the
tissue microenvironment will be monitored in primary melanomas and LNs as described above
and by in vivo multiphoton microscopy.
2. A) B16-luc overexpressing CCL20 (B16-luc-L20) and appropriate empty vector control cells will
be injected s.c. into WT and CCR6 KO mice to study local immune cell infiltrates, tumor
vascularisation and cytokine profiles (IHC, FACS RT-PCR, ELISA). Also, melanoma cells
derived from B16-luc-L20 primary melanoma will be analysed for mechanisms of apoptosis
resistance B) The effect of topical immunmodulators (i.e. TLR7- agonist imiquimod, DNCB) on
CCL20/ ß –defensin expression, immune cell recruitment and tumor kinetics will be studied
within the experimental setting and methods described above in B16-luc transplanted
melanomas and melanomas of Ret-mice. Also, the effects of intratumoral injections of a
blocking anti-mCCL20 antibody will be studied in both murine models.
3. Paraffin embedded human primary melanoma and LN metastases will be analyzed by IHC for
CCL20 and ß -defensin expression as well as phenotype and distribution of an (CCR6expressing) immune cell infiltrate. Correlation with pathomorphological patterns, disease stage
and tumor progression will be performed.
4.3 Collaborations with other Projects within the RTG
Our project will utilize bioluminescence imaging (Project 7), multiphoton microscopy (Project 6) and
the Ret-mouse model system (Project 13) in close collaboration. Mechanisms of apoptosis
resistance in B16-luc-L20 melanoma will be studied with partners of project 10.
5
1.
2.
3.
4.
5.
References
Lonsdorf AS, Kraemer BF, Fahrleitner M, Schoenberger T, Gnerlich S, Ring S, Gehring S, Schneider SW, Kruhlak
MJ, Meuth SG, Nieswandt B, Gawaz M, Enk AH, and HF Langer. 2012. Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3
mediates interaction of melanoma cells with platelets - a connection to hematogeneous metastasis. J Biol Chem
287:2168-2178.
Chien AJ*, Moore EC*, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ, Major MB, Hwang ST, Rimm DL,
Moon RT. 2009. Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in
patient tumors and a murine melanoma model. Proc Natl Acad Sci USA 106:1193-1198. *equal contribution,
alphabetical order
Hedrick MN*, Lonsdorf AS*, Shirakawa AK, Lee CCR, Liao F, Singh SP, Zhang HH, Love PE, Hwang ST, Farber
JM. 2009. CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 119:2317-2329.
*equal contribution, alphabetical order
Huang V, Lonsdorf AS, Fang L, Kakinuma T, Lee VC, Cha E, Zhang H, Nagao K, Zaleska M, Olszewski WL,
Hwang ST. 2008. Cutting edge: rapid accumulation of epidermal CCL27 in skin-draining lymph nodes following
topical application of a contact sensitizer recruits CCR10-expressing T cells. J Immunol 180:6462-6466.
Lonsdorf AS, Kuekrek H, Stern BV, Boehm BO, Lehmann PV, Tary-Lehmann M. 2003. Intratumor CpG injection
induces protective antitumor T cell immunity. J Immunol 171:3941-3946
29
PACKAGE B2
4
Project Plan
4.1 Specific Aims
1. Characterization of CCR6/CCL20-dependent anti-tumor immune responses in primary
malignant melanoma and skin-draining LNs in murine models of melanoma.
2. Identification of local immunmodulatory factors with functional relevance for CCR6/CCL20mediated anti-melanoma immune responses in primary tumors and skin-draining LNs.
3. Correlation of CCR6/CCL20 expression patterns in primary human melanoma and LN
metastasis with respect to disease stage and local tumor progression.
Project 12: Tumor-directed cytotoxicity of proinflammatory human dendritic cells
and natural killer cells in malignant melanoma (MM)
Prof. Dr. Knut Schäkel, Hautklinik, Universitätsklinikum Heidelberg;
PD Dr. Adelheid Cerwenka; Boveri Research Group Innate Immunity, German Cancer
Research Center
Prof. Frederic Geissmann, Center for Molecular and Cellular Biology of Inflammation, King’s
College, London
Short Summary:
There is good evidence that dendritic cells (DC) and natural killer (NK) cells collectively mount a
strong anti-tumor immune responses. However, we have a limited understanding of how these
populations crosstalk with each other and how we can exploit the NK/DC interaction for the therapy
of malignant melanoma. In addition, it is unclear which subtypes of DC are most relevant for
inducing anti-tumor effector functions in the presence and absence of NK cells. A recent study from
the Cerwenka lab demonstrated that the activation of NK cells with inflammatory cytokines such as
IL12/15/18 greatly increases the anti-tumor activity of mouse and human NK cells. The subset of
DC that produces the highest levels of IL-12 was identified CD11c+ slan (6-sulfo LacNAc+) DCs by
the Schäkel lab. These slanDCs are equipped with an outstanding capacity to induce proinflammatory immune defence functions. slanDC were shown to exert a strong antibody-dependent
(ADCC) and an antibody-independent tumor-directed cytotoxicity. They efficiently enhance the NKdirected anti-tumor cytotoxicity but the underlying mechanisms are poorly understood. We
hypothesize that the NK/slanDC crosstalk is highly relevant for executing cytotoxic anti-tumor
responses in the skin. In the proposed project, we plan to analyze the functional consequences
and mechanisms of the NK/slanDC crosstalk in vitro and in a xenograft mouse model of human
melanoma in vivo. In addition, we will analyse the presence of slanDC and NK cells within biopsies
of melanoma patients after treatment with inflammatory agents such as application of the TLR-7
ligand Imiquimod. The results gained in this project could lead to novel therapeutic strategies for
the treatment of MM based on the exploitation of the slanDC/NK crosstalk.
PACKAGE B2
3
State of the Art
The number, the type and the activation status of tumor-associated DCs and NK cells have been
shown to be of direct prognostic value. Malignant melanoma cells often express low levels of MHC
class I and high levels of activating NK cell ligands, and are therefore very efficiently killed by NK
cells. In general, low numbers of NK cells are found in solid tumors but it has been shown that
inflammatory agents such as the application of the TLR ligand CpG can facilitate NK cell infiltration
into mouse solid tumors. DCs can mount a potent direct cytotoxic anti-tumor response. Cytotoxic
DCs were shown to take the lead in inducing a cytotoxic anti-tumor response when MM were
treated with the TLR7-ligand imiquimod. Furthermore, the antibody-dependent cell-mediated
cellular cytotoxicity (ADCC) of DCs and NK cells contributes to the natural tumor surveillance and
may significantly enhance tumor destruction in monoclonal antibody-based immunotherapies with
e.g. trastuzumab.
Schäkel lab : We identified the population of slan (6-sulfo LacNAc+) DCs in humans (Schäkel et al.,
2002). slanDCs are a population of proinflammatory DCs that stand out by their high level
production of IL-12, IL-23, TNF-α and IL-1ß in response to TLR7 and TLR8 ligation (Hänsel et al.
2011 and 2012). slanDCs have a marked tumor-directed ADCC, and strongly enhance the
cytotoxic capacity of NK cells (Schmitz et al., 2005). The role of proinflammatory or cytotoxic
slanDCs in tumor tissue and their local interplay with NK cells has not been investigated so far.
Cerwenka lab: Our previous study (Ni et al, JEM 2012) revealed that adoptive transfer of NK cells
that were preactivated with IL12/15/18 resulted in greatly increased anti-tumor activity in mouse
models of RMA-S lymphoma and B16 melanoma compared to NK cells pretreated conventionally
30
with IL15 or IL2. Importantly, human NK cells activated with IL12/15/18 also displayed sustained
effector function and higher cell recoveries. To investigate the in vivo anti-tumor activity of human
NK cells, we have established a mouse xenograft model in which luciferase-expressing human
melanoma cells can be imaged in vivo after injection into NSG mice. In addition, our lab has a
long-standing expertise in the investigation of activating receptors expressed by NK cells such as
NKG2D and NKp30 and their ligands expressed by tumor cells (Textor et al, Cancer Res, 2011).
1. We will establish co-cultures of NK cells and DC with a focus on slanDCs. The crosstalk
between these cells types in the absence and presence of TLR ligands will be assessed by
cytotoxicity assays using melanoma cell lines that are well established in our laboratory as
targets. Further experiments will assess the molecules involved in the NK/slanDC crosstalk
(cell surface and soluble factors).
2. Next we will investigate the consequences of the NK/slanDC crosstalk in a xenograft model of
MM. Co-cultures will be established in vitro and primed NK cells (or DC) will be adoptively
transferred into melanoma-bearing mice. Tumor growth and functional parameters of the
transferred cell populations will be monitored. In order to fully activate slanDCs, melanomas will
be treated with Imiquimod.
3. We will conduct a comprehensive analysis to detect slanDCs and the NK cells by Tissue-FAX
in tumor tissues. We will carefully determine the expression of parameters that provide
information about the activation status (iNOS, TNF-α) and the maturational stage of slanDCs
(CD83 versus CD206). The Heidelberg Tumor Registry will provide us with requisite tissue
arrays. We will focus here on melanoma but will compare the obtained data with studies on
SCC and basal cell carcinomas. Attention will be paid to spontaneously regressing tumors, and
tumors regressing following TLR7-treatment.
4.3 Collaborations with other projects in the RTG
For the evaluation of proinflammatory DC and NK cells in melanoma cells we will closly collaborate
with project 13 (on myeloid cell subsets) and project 11 (on cellular recruitment by chemokines).
5
References
1. Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A. 2012. Sustained effector function of IL-12/15/18 preactivated NK
cells against established tumors. J Exp Med 209:2351-65.
2. Textor S, Fiegler N, Arnold A, Porgador A, Hofmann TG, Cerwenka A. 2011. Human NK cells are alerted to induction
of p53 in cancer cells by up-regulation of the NKG2D-ligands ULBP1 and ULBP2, Cancer Res 71:5998-6009.
3. Hansel A, Gunther C, Ingwersen J, Starke J, Schmitz M, Bachmann M, Meurer M, Rieber EP, Schäkel K. 2011.
Human slan (6-sulfo LacNAc) dendritic cells are inflammatory dermal dendritic cells in psoriasis and drive strong
T(h)17/T(h)1 T-cell responses. J. Allergy Clin Immunol 127:787-794.
4. Schäkel K, von Kietzell M, Hänsel A, Ebling A, Schulze L, Haase M, Semmler C, Sarfati M, Barclay AN, Randolph
GJ, Meurer M, Rieber EP. 2006. Human 6-sulfo LacNAc-expressing dendritic cells are principal producers of early
interleukin-12 and are controlled by erythrocytes. Immunity 24:767-777.
5. Schmitz M, Zhao S, Deuse Y, Schäkel K, Wehner R, Wohner H, Holig K, Wienforth F, Kiessling A, Bornhauser M,
Temme A, Rieger MA, Weigle B, Bachmann M, Rieber EP. 2005. Tumoricidal potential of native blood dendritic cells:
direct tumor cell killing and activation of NK cell-mediated cytotoxicity. J Immunol 174:4127-4134.
31
PACKAGE B2
4
Project Plan
4.1 Specific Aims
1. To determine the anti-melanoma activity induced by slanDCs/NK cell crosstalk in vitro.
2. To determine the melanoma-directed cytotoxicity induced by slanDCs/NK cell crosstalk in a
xenograft mouse model in vivo.
3. To determine the presence and the activation state of proinflammatory slanDCs and NK cells in
MM biopsies with and without treatment with the TLR7 ligand Imiquimod.
Project 13: Regulation of tumor-associated macrophage and myeloid-derived
suppressor cell activation and its neutralization in transgenic mouse melanoma
model
Dr. Astrid Schmieder, Dept. of Dermatology, University Medical Center Mannheim;
Prof. Dr. Viktor Umansky, Skin Cancer Unit, German Cancer Research Center (DKFZ) and
Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim,
Dr. Sandra Diebold, King's College London, Peter Gorer Department of Immunobiology, Division
of Immunology, Infection and Inflammatory Diseases, Guy's Hospital, London Bridge, London
Short Summary
Melanoma immunotherapy is not satisfactory due to the accumulation of chronic inflammatory
factors and immunosuppressive myeloid cells such as tumor-associated macrophages (TAM) and
myeloid-derived suppressor cells (MDSC) in tumor lesions. The goal of the project is to better
understand the molecular mechanisms underlying the inhibition of anti-tumor immune responses
mediated by TAM and MDSC, and to design novel therapeutic strategies targeting these myeloid
cells in melanoma. We will study the role of signaling molecules (p38 MAPK and S100A8/A9) and
microRNA in the capacity of TAM and MDSC to inhibit anti-tumor reactivity of T cells. Results of
the project will help to develop novel efficient human melanoma treatments neutralizing
immunosuppression in the tumor microenvironment.
PACKAGE B2
3
State of the Art
Despite the intrinsic melanoma immunogenicity, immunotherapeutic trials were not satisfactory due
to the formation of a complex immunosuppressive network mediated by chronic inflammation
developing in the tumor microenvironment. Such microenvironment (represented by various
cytokines, chemokines and growth factors) can induce a recruitment and expansion of suppressive
immune cells such as TAM and MDSC to the tumor site. It has been shown that the expansion and
activation of MDSC and TAM requires several signaling pathways (p38 MAPK as well as S100
calcium-binding protein A8 and A9). Small non-coding RNAs designated as microRNAs (miR) has
been recently shown to significantly regulate the accumulation and function of TAM and MDSC.
Thus, miR-494 can be induced in MDSC by tumor-derived TGF-β supporting immunosuppression
and metastasis. On the other side, miR-511-3p was reported to modulate genetic program of TAM
limiting their protumoral functions. Transgenic mice overexpressing human receptor tyrosine
kinase Ret in melanocytes spontaneously develop skin melanoma with metastases in lymph
nodes, lungs, liver, brain, and bone marrow and can be used for studying melanoma progression in
vivo.
3.2 Previous/preliminary work by the participants
To address the role of MDSC in melanoma progression in clinically relevant conditions, we used
the ret transgenic mouse model, which mimics human melanoma with respect to clinical
development ensuring natural tumor-stroma interactions. Analyzing Gr1+CD11b+ MDSC in
melanoma lesions and lymphatic organs revealed a remarkable elevation of MDSC frequencies.
Moreover, we found increasing concentrations of IL-1β, VEGF, IL-6 and GM-CSF in tumors during
their progression. MDSC enrichment was accompanied by a decrease in TCR ζ-chain expression
in tumor-infiltrating T cells. Therapy of melanoma-bearing mice with the phosphodiesterase-5
inhibitor sildenafil led to decreased numbers and immunosuppressive function of MDSC as
reflected by the restoration of ζ-chain expression and significantly increased mouse survival. In
addition, we identified in subcutaneous murine melanomas TAM that eco-express not only stabilin1 and LYVE-1 but also the novel surface marker MS4A8A, a molecule involved in differentiation
processes. In vitro, these TAM were selectively induced via activation of the p38 MAPK and
32
glucocorticoid signaling pathways, indicating an important role of the p38 MAPK pathway also for
the regulation of TAM activity.
4
Project Plan
4.1 Specific Aims
Aim 1: Investigating signaling molecules and miR involved in the recruitment, expansion and
activation of TAM and MDSC during melanoma progression
Aim 2: Studying the neutralization of immunosuppression induced by TAM and MDSC using the
modulation of their relevant signaling pathways and miR
4.3 Collaborations with other projects in the RTG
For the evaluation of the recruitment and activation of TAM and MDSC in the melanoma
microenvironment, we will closely collaborate with project 11 (CCR6/CCL20 interaction) and
project 12 (proinflammatory dendritic cells).
5
References
1. Schmieder A, Schledzewski K, Michel J, Tuckermann JP, Tome L, Sticht C, Gkaniatsou C, Nicolay JP, Demory A,
Faulhaber A, Kzhyshkowska J, Géraud C, Goerdt S. 2011. Synergistic activation by p38MAPK and glucocorticoid
signaling mediates induction of M2-like tumor-associated macrophages expressing the novel CD20 homolog
MS4A8A. Int J Cancer 129:122-132.
1. Schmieder A, Michel J, Schonhaar K, Goerdt S, Schledzewski K. 2012. Differentiation and gene expression profile
of tumor-associated macrophages. Semin Cancer Biol 22:289-297.
2. Schmieder A, Schledzewski K, Michel J, Schönhaar K, Morias Y, Bosschaerts T, Van den Bossche J, Dorny P,
Sauer A, Sticht C, Géraud C, Waibler Z, Beschin A, Goerdt S. 2012. The CD20 homolog Ms4a8a integrates pro- and
anti-inflammatory signals in novel M2-like macrophages and is expressed in parasite infection. Eur J Immunol
42:2971-2982.
3. Meyer C, Sevko A, Ramacher M, Bazhin AV, Falk CS, Osen W, Borrello I, Kato M, Schadendorf D, Baniyash M,
Umansky V. 2011. Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor
immunity in transgenic mouse melanoma model. Proc Natl Acad Sci USA 108:17111-17116.
4. Zhao F, Falk C, Osen W, Kato M, Schadendorf D, Umansky V. 2009. Activation of p38 MAPK drives dendritic Cells
to become tolerogenic in ret transgenic mice spontaneously developing melanoma. Clin Cancer Res 15:4382-4390.
33
PACKAGE B2
1. We will test the expression and activation (phosphorylation) of such signaling molecules as
S100A8/A9 and p38 MAPK in F4/80highCD11b+Gr1- TAM and CD11b+Gr1+ MDSC in melanoma
lesions and lymphoid organs using FACS. Differentially up- and down-regulated miR in TAM
and MDSC will be studied by Affymetrix Microarray analysis and real-time quantitative PCR.
Functional relevance of identified miR will be analyzed using lentiviral constructs. TAM and
MDSC will be characterized by the expression of arginase-1 and inducible nitric oxide
synthase. The activity of these myeloid cells will be determined by the inhibition of T cell
proliferation upon the co-culture with TAM and/or MDSC. Inflammatory factors (VEGF, IL-1β,
IL-6, TNF-α, TGF-β, etc.) will be detected in melanoma lesions by multiplex technology. Tumorinfiltrating T cells will be validated measuring the ζ-chain expression by FACS.
2. We will suppress signaling pathways involved in the expansion and activation of MDSC and
TAM with specific inhibitors p38 MAPK (SB203580 and RO3201195). Activating miR will be
blocked by the sponge preventing the interaction of this miRNA with its targets. TAM or MDSC
isolated from melanoma lesions will be treated with these inhibitors followed by co-incubation
with activated syngeneic T cells. T-cell proliferation and ζ-chain expression will be tested by
FACS.
4
4.1 Qualification Program
Clinical researchers have to combine clinical expertise with a thorough understanding of the
underlying molecular mechanisms that are altered in disease. Basic scientists with a future career
in academic medicine (or affiliated research institutes) or in industry are more competitive if they
have a sound clinical understanding of the diseases they work on. This is particularly true for
cancer research and especially for the specialized field of dermato-oncology. The RTG will
therefore establish a multi-disciplinary approach to teach cancer biology and dermato-oncology. To
this end, the RTG will on the one hand build on the existing academic and teaching strengths of
the Rhein-Neckar Region with several Graduate Schools of the Medical and Life Science Faculties
of Heidelberg University and of the DKFZ, and on the other hand will offer additional teaching in a
broad range of topics covering the diverse fields of clinical and experimental dermatooncology.
With respect to existing Graduate Schools, Heidelberg University runs the Hartmut HoffmannBerling International Graduate School of Molecular and Cellular Biology (HBIGS) as part of the
Excellence Initiative. The DKFZ runs the Helmholtz International Graduate School for Cancer
Research (HIGS). Students in the RTG will be granted access to the two Graduate Schools, and
the teaching offered by these schools will be integrated into the structured program of the RTG,
which will focus on clinical and scientific aspects of dermatooncology. HBIGS will be responsible
for teaching and training the PhD/MD students in general molecular and cellular biology and in
“soft skills”, whereas HIGS will be responsible for the teaching program in cancer biology and
general oncology. The added value the RTG will provide for the PhD/MD students will be the
application of the general principles and approaches of cancer biology and oncology (the hallmarks
of cancer) to the specific problems and questions of skin cancer biology and dermato-oncology
(the hallmarks of skin cancer) as shown in Figure 1.
Figure 1: Synergy between the RTG
Hallmarks of Skin Cancer, the Hartmut
Hoffmann-Berling International Graduate
School of Molecular and Cellular Biology
(HBIGS), and the Helmholtz International
Graduate School for Cancer Research
(HIGS).
PROGRAM
The teaching program for the RTG students will comprise regular seminars, courses, workshops,
and scientific meetings that will be offered for PhD students in a structured sequence over a threeyear period. MD students will be enrolled into the RTG for 1 year and will participate in all teaching
activities offered to the PhD students. Limitation of their term to one year will make careful
selection of the available training opportunities necessary. This will be supported by mentoring and
advice given by the responsible PIs and MD supervisors.
The seminars will focus on general aspects of oncology (HIGS) and special aspects of
dermatooncology (RTG), while the course/workshop program will offer methodological training in
general techniques in cell and molecular biology (HBIGS, HIGS) and special techniques in
dermatooncological research (RTG). The latter courses will include a mandatory 1-week laboratory
teaching course per year. Soft skill training will be part of the program offered both by HBIGS and
HIGS (Table1-3, see below). While the seminar series and the annual 1-week lab teaching courses
will follow a given structured program, the courses and workshops may be freely chosen by the
students according to their interests and educational needs.
To allow the students of the RTG to fully exploit the teaching on offer, each RTG student will be
allowed to attend all seminars, courses and workshops of both HBIGS and HIGS. Formally, each
student will therefore become a member of either HBIGS or HIGS in addition to being a member of
the RTG. The teaching program of the RTG reflects the basic idea that each area of the graduate
school and their partners at the DKFZ (HIGS) and Heidelberg University (HBIGS) should equally
contribute to the progress of the respective student/scientific group. Therefore, participation of all
graduate students, associate students, and PIs in the teaching program is considered essential.
Facilitating the communication with HBIGS, HIGS, and the RTG, several members of the RTG are
34
affiliated members of HBIGS (H.Augustin, Angel, Boutros, Leverkus, Goerdt, Sleeman, Schäkel,
Utikal) and/or HIGS (H. Augustin, I. Augustin, Angel, Boutros, Utikal).
4.1.1 Seminars
Table 1: Topics of the different Seminar Series (exemplified)
STATE OF THE ART IN DERMATOONCOLOGY (RTG; PREFERENTIALLY 1ST
YEAR)
Several seminar series will be held to expose the students to all aspects of dermato-oncology. To
start with, there will be a series of lectures on the principles of general and molecular oncology
within the framework of HIGS (“Progress in Cancer Research Lectures”). Within a three-year term,
this seminar series will introduce all departments of the DKFZ in Heidelberg and their research
topics. Covering the different aspects of clinical and experimental dermato-oncology, the members
of the RTG will give a structured seminar series over the course of the three-year program, starting
with general aspects and problems of dermato-oncology in the first year. The lectures during the
second and third year of the RTG series will be selected to preferentially deal with current topics in
dermato-oncology and skin cancer. The seminar series will increasingly include the review of
timely research papers pertinent to the projects of the RTG that will be performed by the students
of the RTG, or may also represent current hot research topics (research lectures). The seminars of
the 2nd and 3rd year will include presentations by international guest lecturers. In order to learn the
conduct and the procedures of international collaboration in science, the students will be given the
opportunity to invite, guide, and introduce the international speakers. When the seminar is given by
a guest lecturer, the students will be given the possibility for discussion after the meeting (“meet
the professor”, 0,05 ECP/h). A selection of topics of the seminar series is listed above (Table 1).
4.1.2 Laboratory Instruction
Hands-on laboratory instruction will be provided by modular laboratory teaching courses (0,1
ECP/h). The annual 1-week laboratory course will be mandatory for all students (Table 2).
35
PROGRAM
CURRENT TOPICS IN DERMATOONCOLOGY (RTG; PREFERENTIALLY 2ND
AND 3RD YEAR)
Immunotherapy of Skin Cancer
Vascular Oncology
Squamous Cell Carcinoma (Leverkus)
(Umansky)
Innate Immunity/Inflammation and
Cell death pathways for skin
Malignant melanoma (Utikal)
Cancer
tumorigenesis (Leverkus)
Development of pigmentation,
Cytoplasmic signaling Circuitry in
Merkel cell carcinoma (Ludwig)
pigment cell nevus and melanoma
Cancer cells
(Utikal)
How to overcome cell death
Cancer Genetics
Cutaneous Lymphoma (Felcht)
resistance in skin tumors (Geserick)
General dermatopathology of skin
Epithel-mesenchymal transition in
Cancer Epigenetics
tumors (Géraud)
skin cancer (Sleeman)
Oncogenic signaling in skin cancer
Mitosis and Differentiation
Mesenchymal skin tumors (Goerdt)
(Boutros, Leverkus)
Mechanisms of Apoptosis and cell
Cell Migration and Tissue Formation
Basal Cell Carcinoma (Leverkus)
death resistance in lymphoma
(Felcht)
The concept of rational treatment of
Vascular Oncology in skin cancer
Mechanisms of Cell Death Resistance
cancer (Utikal)
(Augustin H, Schneider, Géraud)
Tumor immunology in melanoma
Oncogenic Signaling
Rare cutaneous tumors (Ludwig)
(Umansky, Lonsdorf, Schäkel, Enk)
Innate Immunity/Inflammation and
Animal models for studying melanoma
Cancer Genome Biology
Skin Cancer (Schmieder, Goerdt,
(Sleeman)
Schäkel)
The lymphatic system in dermatoSpezialized dermatopathology of skin
Stem Cells and Cancer Stem Cells
oncology (Sleeman)
tumors (Géraud)
Animal models for the study of basal
Stem cells in normal skin and skin
Tumor Immunology
cell carcinoma (Leverkus)
cancer (Sprick)
Animal models for studying squamous Mechanisms of metastasis formation
Metastasis
cell carcinoma (Angel)
in skin tumors (Schneider)
PROGRESS IN CANCER RESEARCH
(HIGS)
Table 2: Annual 1-week Laboratory Teaching Courses (mandatory)
YEAR 1
YEAR 2
YEAR 3
BASIC LABORATORY TECHNIQUES
IMMUNOLOGICAL METHODS
ADVANCED LABORATORY
TECHNIQUES
DAY 1
DNA and Sequencing
techniques
Antibodies (generation, quality
control and applications)
Next generation sequencing
DAY 2
PCR
T-cells
DAY 3
Basic biochemical Methods
Dendritic cells/Macrophages
DAY 4
Flow cytometry
Chemotaxis, Adhesion
and Transmigration
High throughput RNAi
techniques
Transfection, transduction, and
Reporter Gene Assays; Basic
Proteomics
CRISPR/Cas9 mediated
mutagenesis
DAY 5
Immunohistology/-fluorescence,
LSM
Animal / Genetic models in
Cancer Immunology
Generation of
transgenic/knockout animals
ORGANIZATION
LEVERKUS
MAHNKE
I. AUGUSTIN/BOUTROS
Numerous 2-day hands-on Laboratory Courses covering special topics will be available through
HBIGS, HIGS, or the RTG (0,1 ECP/h; Table 3). In selecting lab courses, we will allow the
graduate students a maximum of flexibility. The PIs will coach the students in choosing individual
courses, but the individual selection process will also require that the students take responsibility to
plan the educational program that will best fit their special interests and needs. This individually
tailored modular system of block courses will allow the students to best take advantage of the
multitude of offers provided by HBIGS, HIGS, and the RTG. While the strength of the HBIGS
and/or HIGS courses are in the broad coverage of all technical aspects of basis research, the RTG
will complement this laboratory instruction with topics relevant in skin cancer research. These RTG
courses will be held in the laboratories of the PIs or co-PIs. Examples for such specialized
dermatooncological lab techniques are tissue-specific culture of endothelial cells, organotypic
cultures of skin cells, or methods for differential cell death detection (Table 3). In addition, the
modular concept allows adaptation to the specific needs also of the MD students.
Table 3: 2-day hands-on Laboratory Courses (Selection of Courses offered)
GENERAL TOPICS IN CELL BIOLOGY AND MOLECULAR
BIOLOGY (HBIGS)
PROGRAM
High-throughput screening for cancer target
discovery
TOPICS PERTINENT TO SKIN CANCER RESEARCH
(RTG)
How to isolate and work with human endothelial
Cells (Felcht, Augustin)
Isolation of primary lung microvascular endothelial
cells from mice and rats (Géraud, Goerdt)
Isolation of primary liver sinusoidal endothelial
cells from mice and rats (Géraud, Goerdt)
Confocal laser scanning microscopy
Multicolor flow cytometry
Advanced FACS sorting techniques
Angiogenesis assays (Felcht, Augustin)
5 Multicolor FACS staining and sorting for stem
cells/cancer-stem cells
Lymphatic vessels (Wholemount staining,
lymphatic ring assay) (Sleeman)
How to simulate in vivo blood flow conditions by
using microfluidic assays (Schneider)
Multi Photon Microscopy
Analysis of gene expression (RQ-PCR, in situ
hybridization)
Generation of IPS cells (Utikal)
Rapid one-step mutagenesis of plasmid DNA
Isolation and culture of primary melanocytes and
melanoma cells (Utikal)
High throughput screens
Assays for tumor invasiveness (Sleeman, Angel)
Orthotopic and Metastatic Mouse Models for
Human Cancers (Sleeman)
Genetic mouse models for malignant melanoma
(Utikal, Umansky)
Mouse models for squamous cell carcinoma
(Angel)
Analytical Ultracentrifugation
Animal handling
State of the art Imaging techniques
Magnetic cell sorting
Functional studies of human DCs (Schäkel)
36
4.1.3 Workshops
The workshops serve to teach theoretical topics of general importance in pursuing research work,
as well as key competences or “soft skills”. For most of the “soft skill” topics there will be courses
offered within HBIGS and HIGS. Examples include learning strategies, scientific writing, presenting
and rhetorical skills, interpersonal skills, entrepreneurship, and others. In addition there is a close
cooperation with the Masters Program “Translational Medical Research” of the Medical Faculty
Mannheim (coordinator Prof. J. Sleeman, also member of the Steering Committee of the RTG) that
also offers a broad range of training in these “soft skills”. In order to allow the PhD students a
maximum of flexibility for their experimental work, at least 3 workshops covering these “soft skills”
topics should be attended during the 3-year schedule.
4.1.4 Student project development platforms and students’ conferences
While preparing for the 2nd year British-German Workshop on Skin Cancer Biology (see 4.3), the
students will write a structured progress report about their project. Within this progress report they
will be encouraged to suggest how they envision the further strategic and experimental
development of their projects. These project reports and continuation proposals will be discussed
in detail at the Workshop with the PIs and with the London supervisors during the Project
presentation sessions and at the individual TAC meetings. After the Workshop, the students will rewrite the proposals and make them available to the RTG community via the intranet for discussion.
As an additional important active task, the students of the RTG will organize the 3rd year BritishGerman Workshop on Skin Cancer Biology as an international conference covering topics relevant
to the “Hallmarks of Skin Cancer” serving also as a final status/farewell seminar. In this respect,
they will be actively guided by the PIs/Steering Committee.
4.1.5 Transition from the first class of doctoral students to the next class
Since the doctoral program is scheduled for 3 years, recruitment for the second generation of
students will begin about 2.5 years after the start of the program. Before that, opportunity to join
the programme will be given annually to associated doctoral students, for whom the same rules
and rights will apply as for the regular students – except for funding by the RTG. Most parts of the
program do not have to be taken in a specific temporal order. Those parts that have to be taken at
the beginning or end of an individual schedule will be offered annually (legal, ethical matters).
Each participating group will invite national and international expert scientists during the funding
period. Emphasis will be put on individuals who have an outstanding reputation in the fields of skin
carcinogenesis, skin tumor progression and metastasis, vascular biology, cell signalling, cancer
target research and tumor immunology. Given the time constraints of top researchers, these visits
will typically last for no longer than 3 days. The visiting program will also enable
Professors/Lecturers from the St. John’s Institute of Dermatology and other groups in London to
visit the PIs and graduates in Mannheim/Heidelberg, and consult about ongoing projects.
4.3 Additional qualification program: scientific collaboration with the London
project partners of the RTG
As science is an international endeavor, the RTG aims to introduce the students to international
scientific collaboration. To this end, the RTG has set up the participation of an inter-institutional
scientific faculty in the Metropolitan Area of London centered around the St. John´s Institute of
Dermatology and King’s College. The faculty comprises high-ranking scientists of the St. John´s
Institute of Dermatology, King’s College, the University of London and Cancer Research UK who
are committed to the goals of the research program of the RTG, and who have outstanding
expertise across the spectrum of relevant basic, translational, and clinical science. Each RTG
project will be assigned a London project partner including Dr. Joy Burchell, Dr. Sandra Diebold,
Prof. Anthony Dorling, Prof. Frederic Geissmann, Prof. Adrian Hayday, Prof. Frank Nestle, Prof.
Fiona Watt, Prof. Sean Whittaker from King’s College; Prof. Fran Balkwill, Prof. Ian Mackenzie,
Prof. Kairbaan Hodivala-Dilke from Queen Mary University of London; Prof. P. Meier from the
Institute of Cancer Research; Prof. Henning Walczak, Prof. Buzz Baum from University College of
London; and Dr. Ilaria Malanchi and Dr. Caroline Hill from London Research Institute, Cancer
37
PROGRAM
4.2 Guest scientist program
Research UK. The input the London project partners will give to the scientific collaboration and the
scientific carreer development of the students will be twofold:
(1) Most importantly, the London project partners are committed to host the respective PhD/MD
students for a variably long (6-week to 6-month), project-adapted lab visit to conduct part of the
experiments for their thesis projects in London. This lab visit will heavily impact on the scientific
development of the students offering them the opportunity to learn new techniques and to re-shape
their projects due to the discussions with and the advice from the London project partner.
(2) During the 3-year course of a PhD student’s life in the RTG, the RTG will organize a yearly
“British-German Workshop on Skin Cancer Biology” in which the London project partners actively
participate. In the first year, following recruitment of the students, the RTG will hold the 1st “BritishGerman Workshop on Skin Cancer Biology” in Mannheim to introduce the students to each other,
to the Faculty of the RTG and to the London Faculty. The Workshop will include plenary lectures
from selected London project partners, short project presentations by the students, the introductory
course “How to design a scientific project”, and inaugural, parallel Thesis Advisory Committee
(TAC) meetings. The 2nd “British-German Workshop on Skin Cancer Biology” will last 4 days, will
be organized by the London partners in London and focus on the specific competence and
scientific excellence of the London partners and their institutions.
Table 4: Schedule of the 2nd-year “British-German Workshop on Skin Cancer Biology” in London
16 hrs= 1 ECP
1st day
Key note lecture
9
10
11
2nd day
Arrival
3rd day
Lecture
Cancer Stem Cells
(F. Watts)
Science structure and
Funding opportunities in
UK
Coffee
Break
Selected
project presentations
Selected project
presentations
(incl. MD projects)
4th day
Key note lecture
γ δ T cells in tumor
immunity (A. Hayday)
12
Key note lecture
13
Modern Methods in
Translational Oncology
(F. Nestle)
Parallel TAC Meetings
Lunch break
14
15
Key note lecture
Selected project
presentations
(30 minutes per project)
(10 min introduction PI,
10 min presentation of the graduate,
10 min plenary discussion)
Site Visit
Selected project
presentations
(London Partners)
to the
Francis Crick Institute
Tumor Angiogenesis
(K Hodivala-Dilke)
PROGRAM
16
Site Visit
17
to the
St. Johns Institute
18
Key note lecture
Genetics of Skin Cancer
(J. McGrath)
Scientific Lectures
(London Partners
within the
Departure
Francis Crick Institute)
All London project partners will attend this Workshop in London to allow for intense scientific and
project-related interactions and discussions in the unique scientific environment of the London
Faculty accompanied by the TAC meeting of the second year (see table 4). In the third year and as
an additional important active task, the students of the RTG will organize the 3rd “British-German
Workshop on Skin Cancer Biology” as an international 3-day scientific conference “Hallmarks of
Skin Cancer” in Heidelberg which will also serve as a final status/farewell seminar. In this respect,
they will be actively guided by the PIs/Steering Committee; the London project partners will also
play an active role in this international scientific dermato-oncology conference.
4.4 Only Regarding International Research Training Groups: Research Stays at the
Partner Institution
Does not apply
38
5
Supervison and career development, equal opportunity / gender
equality, organization, and quality management
5.1 Application and selection concept
Recruitment of the best PhD and MD students is central to the success of the RTG. For the PhD
studentships, the open positions will be advertised internationally via appropriate journals and
scientific job platforms on the internet by the RTG in cooperation with HBIGS and HIGS. Each PI
will also individually advertise his/her PhD position. The highly standardized admission procedures
of HBIGS and HIGS will be extremely helpful for the selection of the best educated and most
ambitious candidates, especially from foreign countries. Applications for each project either preselected by HBIGS / HIGS or on an individual basis will then be evaluated by the co-PIs as well as
by representatives of the RTG (managing board) to ensure that standard high quality selection
criteria are applied, including equal opportunity. For the MD recruitment process, the RTG will
primarily rely on the local MD/PhD programs to identify the top MD students for a 1yr thesis project,
including the scientific part of the Reformed Medical Study Program of the Medical Faculty
Mannheim, MARECUM, i.e. the Junior Scientific Master Class Program and the Translational
Medical Research Master Program (TMR). MD students are increasingly difficult to recruit for
ambitious doctoral programs, and we have therefore only included 8 MD positions per year.
Supervision, mentoring and RTG contract. A structured and individualized supervision concept is
the basis for the success of the RTG. All rights and liabilities of the RTG and the student will be
fixed in a contract signed by the university and the student at entry. The supervision concept will
include the established elements of daily/weekly PI supervision with the active contribution of
graduate students in the weekly group seminars to develop presentation skills and scientific
discussion abilities. The supervisors will meet at least once monthly with each student for intense
exchange and project-specific discussion. Each student will choose a co-supervisor from the RTG
with whom the project progress will be discussed at least annually. The Speaker of the RTG will
keep a permanent record of the credits earned by each student, and will share responsibility for the
progress of the student with the supervisors. Additional external mentoring will be provided for
each graduate student by assigning them an external co-supervisor within the framework of the
collaboration with the inter-institutional London RTG Faculty. This mentoring program will include
individual counseling during the British-German Workshops on Skin Cancer Biology and the lab
visit to the external mentor’s laboratory. In case of the need for more intense or specific
counseling, individual meetings with the London co-supervisor will be arranged. This multiple level
mentoring program will facilitate continuous and focused supervision of the graduate student, and
will allow timely intervention to guarantee the graduate student’s best scientific and educational
development.
Students’ Performance. To continuously evaluate the progress of the student, the RTG will
implement a credit point system. The graduates will be expected to collect a defined number of
credit points (60 ECP) per year. Should a graduate student not obtain the required number of
points, the PI and the Speaker of the RTG will be responsible to interview the student. It is
expected that the graduate students devote approximately 10 - 15% of their working time to the
structured educational program of the RTG. Altogether the graduate students should earn at least
180 ECP during their 3-year thesis work. Of these, 50 ECP will be granted annually for the
continuous experimental work on the thesis project, while 10 ECP annually must be collected by
participation in the educational program. Depending on the degree of passive or active
participation, 0.05 or 0.1 credit points will be accredited per hour. Similar to the ECP system of the
RTG, HBIGS and HIGS use ECP to assess the achievements of the students. ECP earned in
courses held by HBIGS or HIGS will be fully accepted by the RTG. MD students admitted to the
RTG will have to earn 60 ECP during their one-year thesis work.
Scientific Independence. Scientific independence is one of the major goals of the supervising
concept of the RTG. This will be specifically supported by the modular teaching system, and
complemented with an obligatory introductory course ("how to design a scientific project"),
presentation and discussion of the project outline during the 2nd-year British-German Workshop on
Skin Cancer Biology, and regular progress reports. The students will be encouraged to actively
engage in the organization of a meeting covering the focus of the RTG. Furthermore, relevant
39
PROGRAM
5.2 Supervising Concept and Career Development
national and international meetings will be announced during the teaching events and via the
intranet, and the graduate students will be encouraged and financially supported to participate in
such meetings and to present their data.
Start-up Grants. Within the framework of the RTG, the most brilliant students will be actively
encouraged to remain within the scientific field of dermato-oncology. The RTG will therefore offer
doctoral students the opportunity of applying for start-up grants when they approach the end of
their PhD work. A transparent application procedure will be implemented to allow these students to
fund their own start-up projects through RTG funds (see 7.8). The previous PI and the
speakers/Steering Committee will closely counsel the applicants. The primary goal of the start-up
grant is to generate sufficient peer-reviewed scientific evidence to support the initiation of an
independent research career. A primary evaluation criterion of start-up grant applications will thus
be whether the proposed project will generate sufficient results to successfully support a
subsequent application for grant funding from the DFG. Start-up grants will either fund local
independent research by the start-up applicant, or will pave the way to other international
laboratories in which the start-up applicant will further deepen his/her knowledge in the selected
scientific field of dermato-oncology.
5.3 Equal opportunity / Gender Equality in Science
The RTG „Hallmarks of Skin Cancer“ will join and strengthen ongoing
activities in Heidelberg University and the German Cancer Research
Center (DKFZ) to balance the relation between male and female
researchers and to support the compatibility of work and family
responsibilities. It will especially take measures to systematically
enhance career development and qualification of young female
scientists. The aims and the status quo regarding the numbers of femal
and male participating MD/PhD student and researchers are found in
tables A and B.
A. MD/PhD students
%
Aim
MD/PhD
students
m
f
(40-60
%)
(40-60
%)
PROGRAM
Measures already taken by the University of
Heidelberg. The PIs, postdoctoral fellows and the B. Participating Researchers
students of the RTG „Hallmarks of Skin Cancer“ will be
Number
%
supported by
the ’Gleichstellungsbüro’ (Equal
Status Quo
Status Quo
Opportunities Office) of the University, by the Equal
Opportunities Offices of the Medical Faculties and of the
m
f
m
f
DKFZ. Here many measures are already being taken to
realize gender equality, to enhance the careers of Junior PIs
3
3
50
50
women especially in their initial stages, and to support
female and male scientists with children. The University Senior PIs
12
1
92.3
7.7
has implemented a gender action plan that specifies
targets and management by objectives in order to
15
4
79
21
steadily improve gender equality in all departments. We Total
refer
to
http://www.uniheidelberg.de/einrichtungen/gleichstellung.html for a comprehensive documentation. According to
the recent evaluation by the DFG, Heidelberg University has reached Step 4 regarding the
implementation of the “Forschungsorientierte Gleichstellungsstandards der DFG”.In
particular the following measures have already been realized within the above institutions and all
members of the RTG agree to participate.
The Olympia Morata Program of the University of Heidelberg supports “habilitations” of female
scientists by financing 0.5 VK of their own position (TVL E13) reducing their routine workload. The
program is open for participation by the female members of the RTG „Hallmarks of Skin Cancer“,
and it will enable them to continue and advance a career in science. A specific mentoring and
training program for female researchers within the life sciences is organized by the equal
opportunities commissioner in cooperation with the Faculties of Medicine and the DKFZ, which
targets the transition phase from the doctoral to the postdoctoral period, and aims to educate and
prepare women for leadership in a career in science. Furthermore, various training events and
meetings for young scientists such as Wi MEET are organized to support the networking of young
female scientists in order to integrate them into the scientific community.
40
Measures to support the career of scientists with children. By offering a total of 407 places for
children (in the age range from 2 months to 6 years) Heidelberg University wants to attract more
female scientists to long-term academic careers. In cooperation with the University, the RTG
„Hallmarks of Skin Cancer“ will offer custom-made services to support young scientists who have a
family. This includes both full-time child care (Kinderhaus) and a ‘just in time’ or ‘back-up’ care
initiative (KidsClub). Currently, the RTG has reserved places especially for use by its members.
The RTG „Hallmarks of Skin Cancer“ is thus well prepared to provide child care services to its
doctoral researchers, and its members can also participate in the University’s Concierge Service,
which helps to reconcile academic work and domestic duties..
Measures already taken by the German Cancer Research Center and HIGS. Since 2005, the
DKFZ has implemented an “Audit Work und Family” (Audit Beruf und Familie) procedure, a
strategic management tool to help facilitate a better work-life balance for employees. Numerous
opportunities are offered to all members of the DKFZ to promote compatibility between work and
family life, and equal opportunities. These include child-care places, a mother-child room,
mentoring programs at several levels of the career and “dual-careers” support. The gender ratio of
HIGS is well balanced (57% female). However, despite the high representation of females among
the students, the number of women in leading positions at the DKFZ is much lower. At HIGS, this
imbalance is openly discussed and addressed during the PhD training. Support for women in
science is provided by the DKFZ Executive Women’s Initiative, which focuses specifically on
requirements of female scientists as they seek to obtain leadership positions in science. Several
HIGS-specific measures exclusively for PhD students exist to ensure work-life balance and equal
opportunities. HIGS currently offers up to six subsidized child-care places to PhD student parents
at the Glückskinder day-care center close to the DKFZ. Furthermore, the PhD Careers Service
offers a large range of courses and seminars to PhD students, encompassing themes relating to
work-life balance planning and promotion of women in science.
Measures made for and to be realized within RTG „Hallmarks of Skin Cancer“
All members of the RTG will be encouraged to participate in the above-mentioned programs for
gender equality and family support offered by Heidelberg University and the German Cancer
Research Center, and will receive financial support to do so. In addition, the following measures
will be realized as part of the RTG program.
•
•
•
Recruitment and Motivation of Female Candidates. During recruitment of candidates for the
PhD/MD positions the RTG will clearly announce that female applications are highly welcome
and that the RTG especially supports the career development of female scientists. All members
of the consortium will pay particular attention to recruiting talented female undergraduates and
MD students to the RTG who attend their lectures.
Networking. In close cooperation with the RTG, the University’s Graduate Academy and the
equal opportunity commissioners of the University and the DKFZ will support the organisation
of regularly held workshops to bring the female students of the RTG into close contact with a
network of experienced female postdoctoral researchers in and beyond the field.
International Orientation. The RTG will provide dedicated financial support for visiting female
researchers to foster exchange of scientific ideas and to facilitate international networking.
These meetings will provide the opportunity for female students to get directly in touch with
leading international female scientists. This will have a strongly inspiring and mentoring effect
on our female doctoral and postdoctoral researchers, in line with the strategic targets set by the
RTG and the University. The RTG will furthermore cover travel expenses for female PhD / MD
41
PROGRAM
The Medical Faculty Mannheim (Department of Gender Mainstreaming) has offered
professional consulting for women, parents, students, colleagues in difficult life situations or with
individual problems since 2008. Part-time work and home office work are possible. Day-care for
children aged 0 – 3 started in 2009 (20-22 children) and day-care for children aged 2 – 6 (15-20
children) in 2010. The day-care named MEDI-KIDS is available daily for 12 hours and only closes
for 10 days a year. During holidays, children aged 7 – 12 are invited to join a summer sport camp
(DELTA-KIDS). 2012 a student baby-sitter-service was successfully implemented for members of
the faculty. The RTG requests financial support for gender measures which include various
procedures such as technical support, mentoring activities and complementary child care.
•
students who wish to present their research results and prepare for a subsequent research
stay in a laboratory led by a female scientist who will serve as a role model.
Postdoctoral Support. In order to achieve sustainable effects on career planning and gender
balance, the RTG will provide additional support for the first postdoctoral period of alumni after
their PhD thesis work, with a special focus on gender equality. This support will be awarded on
the basis of a convincing and tight research plan that has been approved by the scientific
committee and supervisors under the auspices of the start-up grants (see 5.2).
Funding by the gender balancing program of the RTG „Hallmarks of Skin Cancer“
The RTG will provide financial support for the following gender equality measures:
• Child care and measures to enhance the compatibility of study, research and family.
• Support by technical assistance in case of long absence (illness, pregnancy).
• Invitation of outstanding female researchers for national and international exchange and
networking with the young talented female participants in the RTG program.
• Seminars preparing female researchers within the RTG program to continue their career far
beyond their PhD and helping them to plan the elements that make up a career in academia,
and to get education for the needed specific skills.
5.4 Organization
To manage the complex task of inaugurating and administering the novel RTG, a three-level
infrastructure will be established comprising the Managing Board, the PI Convent, and the
Students’ Assembly and Students’ Representatives, and other forms of student participation.
PROGRAM
The Managing Board of the RTG comprises the speakers, the secretary, three elected
representatives of the PIs, and three elected representatives of the graduates. The board will meet
every three months on a regular basis and on demand. The board of the RTG will organize the
yearly PI convent and a yearly full assembly of all graduates to discuss administrative matters. The
speaker of the RTG will be responsible for preparing strategic decisions and communication with
the partners in London, as well as with the PIs and the students’ representatives regarding general
matters. The speaker will also prepare the evaluation of the applications for the doctoral positions
within the RTG to be decided by the Managing Board and the respective PIs. The vice-speaker will
serve as a general coordinator. He will be responsible for the day-to-day organization of the RTG.
The secretary of the RTG will serve as a personal assistant to the speaker and the vice-speaker.
She/he will also be actively involved in the organization of the study program, including lectures
and courses and the interaction with the officials in London in organizing the British-German
Workshops on Skin Cancer Biology. He/she will be involved in the inauguration of a structured
procedure for enrolling and registering new graduates, and will take responsibility for the following
issues: studentship contracts, insurance, payment logistics, and short-term housing (for visiting
students and teachers). The Speakers will also evaluate the applications for the rotational positions
and will make a granting decision. Together with the speakers, the secretary will manage the
accountancy of the 13 projects, the budgeting of the teaching program and the settlement of
accounts with the DFG. Together with the vice-speaker and the PIs, the secretary will be
responsible for coordination and organization of lectures and symposia (correspondence regarding
invitations, transfer, housing logistics), establishing and updating the homepage of the RTG
(together with the IT-Manager of the Faculty), design of invitations, brochures, information,
statistical work regarding quality management and students’ affairs, and protocols of meetings.
The PI Convent. The PIs of the RTG projects are full members of the PI Convent, while the
associated PIs are members without the right to vote. Members of the London Faculty are not
formal members of the PI Convent. The PI Convent will elect the three representatives of the PIs to
serve on the Managing Board. The PI Convent will be responsible for deciding general matters of
strategic importance for the RTG including recruitment of new PIs or Projects, and for the
evaluation of the outcome of the RTG and the students’ performance. The PIs will be invited to
convene on a regular yearly basis and on demand by the speaker, and will be informed by the
speaker about the progress of the RTG, current requirements, and future meetings. The results of
these meetings will be regularly communicated to all members of the RTG by the secretary via the
webpage of the RTG.
42
Students’ Assembly, Students’ Representatives and other forms of participation. After the
first 4-8 weeks on campus, the new class of students will convene for a meeting to discuss
organizational matters of the RTG, and the details of the study program. The election of 3 students’
representatives who will be members of the Managing Board, take part in the PI Convent and
report problems and suggestions concerning the whole class to the speakers of the RTG will also
take place at this meeting. The students’ assembly will convene at least once a year and on
demand. The students’ representatives will be (re-)elected every year.
Internal Communication and Public Relations. Effective dissemination of information will be
achieved via the intranet/internet. We will establish a RTG website that contains all information
about ongoing teaching and research activities (e.g. by virtual posters, alerts for recent
publications) and a newsboard with daily updates. This activity will be part of the responsibilities of
the Secretary of the RTG supported by the PR department of the Medical Faculty in Mannheim
(Frau Dr. Wellnitz). In addition, the website will contain a secured internal discussion forum
accessible to RTG members only. In addition, the webpage will contain material and links for
informing the public about skin cancer in general and about the activities of the RTG.
5.5 Additional aspects of quality management
The dynamics of research demand a highly adaptive frame in which young researchers can
develop and mature. Thus, specific measures will be implemented to meet the steadily changing
challenges and needs in the research and qualification program.
1. At the regular yearly British-German Workshops on Skin Cancer Biology, there will be intense
and structured discussions about the progress of the research projects and their future
directions with all members of the RTG and the foreign mentors in London which will give the
PhD/MD students and their PIs as well as the Steering Committee (see Section 2) a continuing
feedback to improve and re-direct the projects. For the selection of MDs, the PI will be obliged
to submit a MD project outline to the steering committee for approval and criticism. Additional
candidate PhD/MD projects for inclusion in the RTG will be reviewed by the Steering
Committee and an external reviewer from the London RTG faculty. Candidate projects should
fulfil the criteria of scientific focus (dermato-oncology), excellence (publications, track record,
extramural funding), qualification (successful thesis supervision), and teaching activities
(workshops, seminars, clinical expertise). After approval, these projects will be considered as
associated projects and will contribute to the further development of the research program of
the RTG.
43
PROGRAM
Other forms of participation. Following recruitment of the students, the RTG will organize the 1st
year British-German Workshop on Skin Cancer Biology, a mandatory inaugural two-day meeting to
introduce the students to the RTG and to each other as well as to the British PIs. This 1st year
British-German Workshop on Skin Cancer Biology will serve to present and discuss the scientific
projects and their status at the beginning of the RTG with the members of the RTG as well as with
the British Co-PIs; it will furthermore include general instructions, and the introductory course “How
to design a scientific project”.
PIs, associate PIs, students, and the members of the Managing Board will meet on a regular
weekly basis to discuss ongoing issues of the RTG and of the students’ career development in the
form of an open, informal “jour fixe” (Wednesday evenings after the seminar series). Such a weekly
meeting of the students together with some of the supervisors will allow for closer interactions and
the initiation of fruitful collaborations within the frame of the RTG. When the first students are on
the brink to graduate, the 3rd year British-German Workshop on Skin Cancer Biology will be
organized as an international students’ conference/final status/farewell seminar by the PhD/MD
students.
The RTG will register all PhD/MD students into either HBIGS or HIGS. HBIGS and HIGS offer
scientific platforms for multiple additional courses that cover a broad spectrum of areas within
cellular and molecular biology of interest to the PhD students of the RTG. Similar to the ECP
system that will be implemented within the RTG, HBIGS uses ECP to assess the participation of
the students within the teaching program. Admission of the PhD student to HBIGS will give the
PhD students a maximum of flexibility while profiting from the broad spectrum of educational
programs in the Rhein-Neckar region.
2. In order to continuously improve the qualification program, feedback will be provided by the
graduates at the regular yearly British-German Workshops on Skin Cancer Biology as well as
during the regular jour fixe, the meetings of the Managing Board and the Steering Committee
as well as in the Students’ Assembly. On this basis, the Managing Board will develop
measures to improve the qualification program and discuss these measures with the PI
convent and the students’ representatives before implementation.
3. Structured data documentation will be implemented from the start of the RTG, and will cover
the following areas: a. application and selection procedures; b. scientific meeting contributions
(meeting abstracts); c. CV-relevant graduate achievements (publications, grants, awards), d.
alumni program (documentation of postdoctoral positions).
4. Success will be measured using the following parameters: adherence to the 3-year qualification
period for PhD students (TTT – time to thesis), numbers of finished PhD / MD theses,
publications in peer-reviewed journals, approved project grants by national/international
foundations, travel grants to congresses, poster awards at conferences, congress participation
by invitation.
6
Scientific Environment
PROGRAM
Cancer is without doubt the major clinical and research focus of both medical faculties of
Heidelberg University. Oncology as a research focus of the University is structurally strengthened
by the close interaction with the German Cancer Research Center in Heidelberg (DKFZ) including
the DKFZ-ZMBH Alliance, by the National Center for Tumor Diseases (NCT) and by the German
Consortium for Translational Cancer Research (DKTK). Heidelberg University together with the
DKFZ is also a unique place to realize the research aims of the RTG as here is the highest
concentration of research and clinical departments devoted to dermatology in general and
specifically skin cancer in Germany. The Depts. of Dermatology in Heidelberg and Mannheim with
Sections for Experimental and Molecular Dermatology, both being certified Skin Cancer Centers,
the Clinical Cooperation Unit Dermato-Oncology of the DKFZ in Mannheim, and the Dept. of Signal
Transduction and Growth Control of the DKFZ are all primarily devoted to research in dermatooncology. Basic research departments of both faculties and the DKFZ with a major research
interest in skin cancer biology, such as the Depts. for Vascular Oncology / Tumor Angiogenesis
and of Signaling and Functional Genomics, further strengthen this Heidelberg-Mannheim Skin
Cancer Alliance.
Despite its major focus on cancer, Heidelberg University does not run a Collaborative Research
Center (SFB), an excellence cluster, another research training group (RTG) or a graduate school
directly in the field of oncology with the exception of the TRR77 “Liver Cancer” which however is in
its running out phase. The SFBs of the University in the field of the life sciences are rather
organized in a mechanism-oriented manner such as the TRR23 “Vascular Differentiation and
Remodeling”, the SFB 873 “Maintenance and Differentiation of Stem Cells”, and the SFB 938
“Enviroment-dependent Control of Immunity”.
With respect to graduate schools, Heidelberg University runs HBIGS as part of the Excellence
Initiative, and the IRTG 1874/1 “Diabetic Microvascular Complications / DIAMICOM” in Mannheim,
while the DKFZ runs HIGS to serve graduate students with a DKFZ-affiliated PI. In order to assure
the excellence of RTG students, admission via HBIGS to either HBIGS or HIGS will be a
requirement. This will also allow the PhD students to obtain the “Dr. rer. nat.” from the Heidelberg
Faculty of the Sciences. Several members of the proposed RTG actively participate in each of the
SFBs / graduates schools mentioned above. HBIGS/HIGS offer an excellent administrative
platform and several of the PIs of the RTG are members of HBIGS and/or HIGS. This should help
to recruit the best candidates for the RTG. Of course, when granted, the RTG would also apply to
be officially recognized as a structured PhD program by the Heidelberg Faculty of Biosciences.
The RTG will ensure that graduate students can take courses in the IRTG “DIAMICOM” and the
integrated research training group of TRR23. This will give them a maximum of learning
possibilities together with the flexibility required for efficient and goal-oriented research practice.
The added value of the RTG is not only a better education of PhD and MD students in the field of
skin cancer that will ensure to attract young researchers into this field, but it will also bring skin
cancer research departments in Heidelberg-Mannheim into a closer collaboration than hitherto
established. Such a truly developed Heidelberg-Mannheim Skin Cancer Alliance may in the future
be the basis for a skin cancer-oriented collaborative research center application to the DFG.
44
6.1 Demarcation from existing SFBs
The RTG does not overlap with any SFB at Heidelberg University.
In contrast to the RTG “Hallmarks of Skin Cancer”, SFB 850 “Control of Cell Motility in
Morphogenesis, Cancer Invasion and Metastasis” at the University of Freiburg concentrates on
general mechanisms of physiological as well as tumor cell motility; skin cancer plays but a minor
role in this consortium. In contrast to the RTG, SFB 773 “Understanding and Overcoming Therapy
Resistance in Solid Tumors” at the University of Tübingen (run out since June 30, 2013) has
focused on analyzing and evading the mechanisms of secondary tumor resistance to established
therapies such as chemo- and radiotherapy; skin cancer played but a minor role in this consortium.
The Melanoma Research Network of the Deutsche Krebshilfe is a nation-wide research consortium
comprising projects that address most aspects of melanoma initiation and progression. In contrast
to the RTG, cutaneous squamous cell carcinoma is not included, and the members of the
Heidelberg/Mannheim Skin Cancer Alliance at present do not hold funded projects in the
Melanoma Research Network. Furthermore, the RTG offers a structured supervision and
qualification program for PhD/MD students while the Melanoma Research Network as a nationwide research consortium does not have such a focus. Therefore, there is no direct overlap of the
RTG with the Melanoma Research Network, but the two consortia complement each other and will
together considerably strengthen the overall impact of skin cancer research in Germany.
6.2 Demarcation from preexisting graduate colleges
Does not apply
7
Modules / Requested funding
7.1 Module Research Training Group
7.1.1 Funding for Staff
7.1.1.1 Funding for PhD students
12 PHD POSITIONS
EUR
458.640
per year
The scientific environment of the proposed RTG is highly competitive with two medical faculties in
Heidelberg and Mannheim, the Faculty for Bioscience in Heidelberg, the DKFZ in Heidelberg, the
EMBL, the Max-Planck-Institute for Medical Research as well as a considerable number of
biomedical and pharmaceutical companies in the (Bio) region. This includes a considerable
number of collaborative research centers, (integrated) research training groups and institutional
graduate colleges/schools. The cost of financial support for a PhD student differs considerably,
ranging from € 1.100 (Medical Faculty Mannheim) for a fellowship, and from 0.5% TVL E13 to
0.65% TVL E13 (SFB938, TRR23) for PhD positions. Most of the PhD students in the
Heidelberg/Mannheim area are offered TVL positions. To ensure maximal attractiveness of the
new RTG positions and high profile recruitment of the best students to do their research work and
biomedical training in the new RTG, we are applying for the most attractive funding option, i.e.
0.65% TVL E13 positions. This will be an essential incentive to out-compete the high number of
other attractive offers from well-renowned laboratories in the Heidelberg-Mannheim area. As the
success of the RTG will highly depend on the quality of the recruited PhD students, it is crucial for
the RTG to make every effort to attract PhD students from among the top 10% of their classes.
7.1.1.2 Funding for MD students
The funding for the 8 MD students of the RTG à € 670,-- for 4.5 years each will be provided by the
Medical Faculties Heidelberg and Mannheim and by the DKFZ. Five MD stipends will be funded by
the Medical Faculty Mannheim, two MD stipends will be funded by the Medical Faculty Heidelberg,
and one MD stipend will be funded by the DKFZ.
7.1.1.3 Funding for postdocs
Does not apply
45
PROGRAM
12 x 0.65 VK TVL E13 for 4.5 yrs
1 PhD position funded by the DKFZ for 4.5 yrs
7.1.1.4 Qualification fellowships
Does not apply
7.1.1.5 Funding for research students and pupils
Does not apply
7.1.2 Consumables and Further Funding
7.1.2.1 Consumables and Small Equipment
CONSUMABLES
EUR
€ 16.500,- per PhD student
per year for 4.5 yrs
214.500
per year
Small equipment
Does not apply
7.1.2.2 Travel costs
Travel costs for PhD students
FUNDING FOR
EUR
PROGRAM
2 British-German Workshops on Skin Cancer Biology in London
(Flight to London (one way)
13 PhD students, 8 MD students; 2 times
€ 300,- per PhD/MD student
Bus trip London – Mannheim (100,- € person)
Accommodation (€160/d) and per diem (€47/d)
London for 4 days, per PhD/MD student
Individual visits to London for scientific collaboration
within the co-PIs’ labs in the 2nd year of the course
(13 PhD students, 1.5 student generations)
Flight to London
€ 570,-- per student
Duration of the lab visit in London from 6 weeks to
6 months, mean 4 months
Auslandszuschlag (€ 779 per month) and
Kaufkraftausgleich (€ 238 per month) in analogy to the
calculations for stipends;
€ 1.017 per PhD student per month
Individual visits to London for scientific collaboration
within the co-PIs’ labs (8 MD students, 4.5 student
generations, of these estimated 25%)
Flight to London €
570,-- per student
Duration of the lab visit in London from 6 weeks to
3 months, mean 2 months
Auslandszuschlag (€ 779 per month) and
Kaufkraftausgleich (€ 87 per month);
€ 868 per MD student per month
Travel to scientific meetings
One meeting per student à € 500,-- (13 PhD, 8 MD)
per year for 4.5 years
12.600
4.200
34.776
11.115
79.326
5.130
15.588
10.500
per year
Travel costs for principal investigators
FUNDING FOR
EUR
2 British-German Workshops on Skin Cancer Biology, London
Flight to London and travel tickets
€ 570,-- per PI (13 PI, 2 times)
Accommodation (€160/d) and per diem (€47/d) in
London for 4 days, per PI (13 PI, 2 times)
46
14.820
21.528
7.1.2.3 Funding for Visiting Researchers
FUNDING FOR
EUR
Guest lecturers (for 1-day seminars; € 500,-- travel costs,
€ 200,-- accommodation, € 300,-- salary)
10 times per year for 4.5 years
10.000
7.1.2.4 Animal Costs
Animal costs will be supported by institutional core funding
7.1.2.5 Further funding
Does not apply
7.1.2.6 Publication costs
EUR
20.000
7.2 Module Substitute
Does not apply
7.3 Module Coordination
COORDINATION OF THE RTG
EUR
0.5 VK TVL E8 for 4.5 yrs
21.900 per year
Foreign Language Secretary (for coordination, students affairs, cooperation with HBIGS,
organization of lectures, seminars, workshops, summer schools, contacts to London partners,
support for gender equality issues, finances, accounts, homepage of the RTG, effectivity control,
see this application 5.4.a)
7.4 Module Rotational Positions
2 ROTATIONAL POSITIONS
EUR
168.000 per year
The proposed RTG heavily relies upon a successful interaction of physician scientists and basic
researchers as mentors for the PhD and MD students. Of the 19 PIs and co-PIs, 11 PIs within 9
projects are physician scientists with a considerable clinical workload. With two rotational positions,
8-9 physician scientists within the 9 projects led by clinical PIs could devote one year totally to
research and supervision of doctoral students in the RTG. Interested physician scientists involved
in the research projects of the PhD or MD students in the RTG are invited to submit an application
to the Speakers of the RTG annually for a one-year rotational full time/half time position with a
project proposal, full CV, publication list, and list of extramural peer-reviewed funding. The
Speakers of the RTG will evaluate the applications and will make a decision based upon criteria of
scientific excellence.
As suggested by the DFG, the Medical Faculty Mannheim will finance one of the rotational
positions from the Grundausstattung provided the other position is financed by the DFG.
7.5 Module Mercator Fellows
Does not apply
7.6 Module Project-Specific Workshops
BRITISH GERMAN WORKSHOPS ON SKIN CANCER BIOLOGY
2 1st year Workshops in Mannheim à € 10.000 each
1 3rd year International Workshop in Heidelberg
7.7 Module Public Relations
Does not apply
47
EUR
20.000
30.000
PROGRAM
2 VK TVÄ TdL Ä1/2 for 4.5 years
7.8 Module Start-up Grants
START-UP GRANTS
EUR
2018-2019
100.000
In order to allow doctoral students from the RTG to continue their research projects after
finalization of their PhD project and to develop their own research project thereafter, we apply for €
100.000,00 of “Start-up Grants” in the years 2018 to 2019. The application and selection
procedures are detailed in Section 5.2 “Start-up Grants”.
7.9 Module Equal Opportunity / Gender Equality
EUR
15.000 per year
Support is requested to specifically aid female PIs and graduates or PIs and graduates with
children if required. Examples are support for experimental work, mentoring activities,
supplementary child care.
Table 1:
Does not apply
Table 2:
HOURS AS
STAFF
PERCENTAGE OF
FULL TIME
NUMBER
DURATION
(FROM – UNTIL)
TVL E13 65%
12
01/04/2015-30/09/2019
-
-
-
TVÄ TdL Ä1/2 100%
2*
01/04/2015-30/09/2019
PhD Student
Postdoctoral Researcher
Module Rotational Positions
PROGRAM
*As suggested by the DFG, the Medical Faculty Mannheim will finance one of the rotational positions from
the Grundausstattung provided the other position is financed by the DFG.
Table 3:
2015
FROM
APRIL
2016
2017
2018
2019
TILL
SEPT.
-
-
-
-
-
SUM
Support Staff (Student Assistents)
-
Equipment up to € 10.000, Software and
Consumables
160.875 214.500 214.500 214.500 160.875
965.250
Travel
11.328
89.213
45.251
15.104
85.437
246.333
Visiting Researchers
7.500
10.000
10.000
10.000
7.500
45.000
Experimental Animals
-
-
-
-
-
-
Other
-
-
-
-
-
-
Publications
-
-
5.000
10.000
5.000
20.000
48
Module Substitute
-
-
-
-
-
-
16.425
21.900
21.900
21.900
16.425
98.550
-
-
-
-
-
-
10.000
-
30.000
10.000
-
50.000
Module Public Relations
-
-
-
-
-
-
Module Start-up Grants
-
-
-
50.000
50.000
100.0010
Module Gender Equality Measures in
Research Networks
11.250
15.000
15.000
15.000
11.250
67.500
SUM
217.378 350.613 341.651 346.504 336.487 1.592.633
Module Coordination
Module Mercator Fellows
Module Project-specific Workshops
(All figures in Euro)
8
Only regarding International Research Training Groups: Complementary
Funding by the partner institution
Does not apply
9
Declarations
9.1 Relations to other SFBs
Does not apply
9.2 Collaboration with other cooperation partners
9.3 Cooperation with corporate partners
Does not apply
9.4 Admission of qualification students
Does not apply
9.5 Submissions of the proposal to other funding organisations
Does not apply
9.6 Only regarding International Research Training Groups: Letter of Intent of the
partner institution
Does not apply
49
PROGRAM
Letters of Intent from the medical faculties of Heidelberg University regarding funding, and of the
London Coordinator, Prof. A. Hayday (King’s College and Cancer Research UK, London) regarding
scientific collaboration, are to be found in the supplementary part of the application.
10
Obligations
In submitting this proposal for an RTG to the DFG, Heidelberg University and the German Cancer
Research Center as well as the participating researchers agree to:





adhere to the rules of good scientific practice,
have adhered to the guidelines regarding publication lists and bibliographies
(cf. appendices I and II),
observe all laws and regulations relevant to the research program and in particular to
attain all necessary approvals, certifications, etc., in a timely manner,
and - if applicable inform the DFG immediately if funding for this undertaking is requested from a third
party. Proposals previously submitted to a third party and proposals involving major
instrumentation must be mentioned in section 9.5 “Proposal submission to other
funding organisations”,
inform the DFG liaison officer of Heidelberg University about the proposal submission,
plan and conduct any experiments involving humans, including identifiable samples
taken from humans and identifiable data, in compliance with the most current versions
of the German Embryo Protection Act (Embryonenschutzgesetz), Stem Cell Act
(Stammzellgesetz), Pharmaceutical Drugs Act (Arzneimittelgesetz), Medical Devices
Act (Medizinproduktegesetz), and the Declaration of Helsinki.
plan and conduct any animal experiments in compliance with the Animal Protection Act
(Tierschutzgesetz) and the Experimental Animals Ordinance (Versuchstierverordnung).
adhere to the provisions of the Genetic Engineering Act (Gentechnikgesetz) with
regard to experiments involving genetically modified organisms (GMOs).
We accept the foregoing conditions and obligations.
By accepting funding, the applicant university and the participating researchers agree to:
a) use the grant exclusively and in a targeted manner to achieve the objectives of the Research
Training Group as specified in the proposal; conform to the relevant regulations of the DFG in
the use and accounting of funds; observe especially the usage guidelines for Research
Training Groups (DFG form 2.22, in German); and not use the grant to finance core support.
PROGRAM
b) submit to the DFG progress reports on the Research Training Group according to the dates
specified in the award letter; participate in the annual survey to evaluate the program; and
present financial accounts to the DFG detailing the use of funds.
11
Signatures
___________________
Prof. Dr. Sergij Goerdt
Designated Speaker
_____________________
Prof. Dr. Martin Leverkus
Designated Vice-Speaker
___________________
Prof. Dr. Otmar Wiestler
German Cancer Research Center
CEO
_____________________
Prof. Dr. Bernhard Eitel
University of Heidelberg
Rector
50
Appendix I
List of Published Research Relevant to the Research Program
PROF. DR. PETER ANGEL
1. Briso E.M., J. Guinea-Viniegra, L. Bakiri, Z. Rogon, P. Petzelbauer, R. Eils, R. Wolf, M. Rincón,
P. Angel, E.F. Wagner. 2013. Inflammation-mediated skin tumorigenesis induced by epidermal
c-Fos. Genes Dev 27:1959-73. (IF 11,7)
2. Durchdewald M., J. Guinea-Viniegra, D. Haag, A. Riehl, P. Lichter, M. Hahn, E.F. Wagner, P.
Angel*, J. Hess. 2008. Podoplanin is a novel Fos target gene in skin carcinogenesis. Cancer
Res 68:6877-83. * corresponding author (IF 7,8)
3. Florin L., J. Knebel, P. Zigrino, B. Vonderstrass, C. Mauch, M. Schorpp-Kistner, A. Szabowski,
P. Angel. 2006. Delayed wound healing and epidermal hyperproliferation in mice lacking JunB
in the skin. J Inv Dermatol 126:902-911. (IF 6,3)
4. Gebhardt C., U. Breitenbach, J.P. Tuckermann, K.H. Richter, P. Angel. 2002. Calgranulins
S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner
and overexpressed throughout skin carcinogenesis. Oncogene 21:4266-76. (IF 6,3)
5. Gebhardt C., A. Riehl, M. Durchdewald, J. Németh, G. Fürstenberger, K. Müller-Decker, A. Enk,
B. Arnold, A. Bierhaus, P.P. Nawroth, J. Hess, P. Angel. 2008. RAGE signaling sustaines
inflammation and promotes tumor development; J Exp Med 205:275-85. (IF 13,8)
7. Klucky B., R. Mueller, I. Vogt, S. Teurich, B. Hartenstein, K. Breuhahn, C. Flechtenmacher, P.
Angel *, J. Hess. 2007. The serine protease kallikrein 6 promotes keratinocyte proliferation and
migration due to induction of E-cadherin shedding. Cancer Res 67:198-206. *corresponding
author (IF 7,8)
8. Peterziel H., J. Müller, A. Danner, S. Barbus, H.K. Liu, B. Radlwimmer, T. Pietsch, P. Lichter, G.
Schütz, J. Hess, P. Angel. 2012 Expression of podoplanin in human astrocytic brain tumors is
controlled by the PI3K-AKT-AP-1 signaling pathway and promoter methylation. Neuro Oncol
14:426-39. (IF 5,7)
9. Tuckermann J., H. Reichardt, R. Arribaz, H. Richter, G. Schütz, P. Angel. 1999. The
dimerization-independent function of the glucocorticoid receptor mediates repression of AP-1dependent gene expression in skin, J Cell Biol 147:1365-1370. (IF 10,2)
51
APPENDIX I
6. Hummerich L., R. Müller, J. Hess, F. Kokocinski, M. Hahn, G. Fürstenberger, C. Mauch, P.
Lichter, P. Angel. 2006. Identification of novel tumour-associated genes differentially expressed
in the process of squamous cell cancer development. Oncogene 25:111-21. (IF 6,3)
PROF. DR. HELLMUT AUGUSTIN
1. Alajati A., A.M. Laib, H. Weber, A.M. Boos, A. Bartol, K. Ikenberg, T. Korff, H. Zentgraf, C.
Obodozie, R. Graeser, S. Christian, G. Finkenzeller, G.B. Stark, M. Héroult, H.G. Augustin.
2008. Spheroid-based engineering of a human vasculature in mice. Nat Methods 5:439-45. (IF
23,57)
2. Felcht M., R. Luck, A. Schering, P. Seidel, K. Srivastava, J. Hu, A. Bartol, Y., Kienast, C. Vettel,
E.K. Loos, S. Kutschera, S. Bartels, S. Appak, E. Besemfelder, D. Terhardt, E. Chavakis, T.
Wieland, C. Klein, M. Thomas, A. Uemura, S. Goerdt, and H.G. Augustin. 2012. Angiopoietin2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest
122:1991-2005. (IF 12,81)
3. Fiedler U., Y. Reiss, M. Scharpfenecker, V. Grunow, S. Koidl, G. Thurston, N.W. Gale, M.
Witzenrath, S. Rosseau, N. Suttorp, A. Sobke, M. Herrmann, K. Preissner, P. Vajkoczy, and
H.G. Augustin. 2006. Angiopoietin-2 sensitizes endothelial cells to TNFα and plays a crucial
role in the induction of inflammation. Nature Med 12:235-9. (IF 24,30)
4. Fiedler U., M. Scharpfenecker, S. Koidl, A. Hegen, V. Grunow, J.M. Schmidt, W. Kriz, G.
Thurston, and H.G. Augustin. 2004. The Tie-2 ligand Angiopoietin-2 is stored in and rapidly
released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 103:4150-6. (IF
9,06)
5. Helfrich I., Scheffrahn, I., Bartling, S., Weis, J., von Felbert, V., Middleton, M., Kato, M., Ergün,
S., Augustin, H. G.*, Schadendorf, D.*.2010. Resistance to antiangiogenic therapy is directed
by vascular phenotype, vessel stabilization, and maturation in malignant melanoma. J Exp Med
207:491-503. (*equally contributing senior authors) (IF 13,21)
6. Hu J., Srivastava, K., Wieland, M., Runge, A., Mogler, C., Besemfelder, E., Terhardt, D., Vogel,
M. J., Cao, L., Korn, C., Bartels, S., Thomas, M., and Augustin, H. G. .2014. Endothelial cellderived Angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science
343:416-9, 2014. (IF 31,03)
APPENDIX I
7. Korn C., B. Scholz, J. Hu, K. Srivastava, J. Wojtarowicz, T. Arnsperger, R.H. Adams, M.
Boutros*, H.G. Augustin*, I. Augustin*: 2014. Endothelial cell-derived non-canonical Wnt
ligands control vascular pruning in angiogenesis. Development, in press. (*equal contribution)
(IF 6,21)
8. Nasarre P., M. Thomas, K. Kruse, I. Helfrich, V. Wolter, C. Deppermann, D. Schadendorf, G.
Thurston, U. Fiedler, and H.G. Augustin. 2009. Host-derived angiopoietin-2 affects early
stages of tumor development and vessel maturation but is dispensable for later stages of tumor
growth. Cancer Res 69:1324-33. (8,65)
9. Thomas M.*, M. Felcht*, K. Kruse, S. Kretschmer, C. Deppermann, A. Biesdorf, K. Rohr, A.V.
Benest, U. Fiedler, H.G. Augustin. 2010. Angiopoietin-2 stimulation of endothelial cells
induces alphavbeta3 integrin internalization and degradation. J Biol Chem 285:23842-9. (IF
4,65) * equal contribution
52
DR. IRIS AUGUSTIN
1. Augustin I., J. Gross, D. Baumann, C. Korn, G. Kerr, C. Mauch, W. Birchmeier, M. Boutros.
2013. Loss of epidermal Evi/Wls results in a phenotype resembling psoriasiform dermatitis. J
Exp Med 210:1761-1777, 2013. (IF 13,21)
2. Augustin I., V. Goidts, A. Bongers, G. Kerr, G. Vollert, B. Radlwimmer, C. Hartmann, C.
Herold-Mende, G. Reifenberger, A. von Deimling, M. Boutros. 2012. The Wnt secretion protein
Evi/Gpr177 promotes glioma tumorigenesis. EMBO Mol Med 1:38-51. (IF 7,80)
3. Korn C., B. Scholz, J. Hu, K. Srivastava, J. Wojtarowicz, T. Arnsperger, R.H. Adams, M
Boutros*, H.G. Augustin*, I. Augustin*. 2014. Endothelial cell-derived non-canonical Wnt
ligands control vascular pruning in angiogenesis. Development, in press. (*equal contribution)
(IF 6,21)
APPENDIX I
4. Voloshanenko O., G. Erdmann , T.D. Dubash , I. Augustin , M. Metzig , G. Moffa , C.
Hundsrucker, G. Kerr, T. Sandmann, B. Anchang, K. Demir, C. Boehm, S. Leible, C.R. Ball, H.
Glimm, R. Spang, M. Boutros. 2013. Wnt secretion is required to maintain high levels of Wnt
activity in colon cancer cells. Nat Commun 4:2610. (IF 10,02)
53
PROF. DR. MICHAEL BOUTROS
1. Augustin I., V. Goidts, A. Bongers, G. Kerr, G. Vollert, B. Radlwimmer, C. Hartmann, C. HeroldMende, G. Reifenberger, A. von Deimling, M. Boutros. 2012. The Wnt secretion protein
Evi/Gpr177 promotes glioma tumourigenesis. EMBO Mol Med 4:38-51. (IF 7.80)
2. Augustin I., D. Baumann, D, C. Korn, G. Kerr, T. Grigoryan, C. Mauch, W. Birchmeier, M.
Boutros. 2013. Loss of epidermal Evi/Wls results in a phenotype resembling psoriasiform
dermatitis. J Exp Med. 210:1761-1777. (IF 13.21)
3. Bartscherer K., N. Pelte, D. Ingelfinger, M. Boutros. 2006. Secretion of Wnt ligands requires
Evi, a conserved transmembrane protein. Cell 125:523-533. (IF 31.98)
4. Boutros M., J. Mihaly, T. Bouwmeester, and M. Mlodzik. 2000. Signaling specificity by Frizzled
receptors in Drosophila. Science 288:1825-1828. (IF 31.03)
5. Boutros M., N. Paricio, D.I. Strutt, M. Mlodzik. 1998. Dishevelled activates JNK and
discriminates between JNK pathways in planar polarity and wingless signaling. Cell 94:109118. (IF 31.96)
6. Cruciat C.M., B. Ohkawara, S.P. Acebron, E. Karaulanov, C. Reinhard, D. Ingelfinger, M.
Boutros, C. Niehrs. 2010. Requirement of prorenin receptor and vacuolar H+-ATPasemediated acidification for Wnt signaling. Science 327:459-463. (IF 31.03)
7. Fuchs F., G. Pau, D. Kranz, O. Sklyar, C. Budjan, S. Steinbrink, T. Horn, A. Pedal, W. Huber,
M. Boutros. 2010. Clustering phenotype populations by genome-wide RNAi and
multiparametric imaging. Mol Syst Biol 6:370. (IF11.34)
8. Gross J.C., V. Chaudhary, K. Bartscherer, M. Boutros. 2012. Active Wnt proteins are secreted
on exosomes. Nat Cell Biol 14:1036-1045. (IF 20.76)
9. Horn T., T. Sandmann, B. Fischer, E. Axelsson, W. Huber, M. Boutros. 2011. Mapping of
signaling networks through synthetic genetic interaction analysis by RNAi. Nat Meth 8:341-346.
(IF 23.57)
APPENDIX I
54
PD DR. ADELHEID CERWENKA
1. Fiegler N., S. Textor, A. Arnold, A. Rölle, I. Oehme, K. Breuhahn, G. Moldenhauer, M. WitzensHarig, A. Cerwenka. 2013. Downregulation of the activating NKp30 ligand B7-H6 by HDAC
inhibitors impairs tumor cell recognition by NK cells. Blood 122:684-93. (IF 9.1)
2. Ni J., M. Miller, A. Stojanovic, N. Garbi, A. Cerwenka. 2012. Sustained effector function of IL12/15/18 preactivated NK cells against established tumors. J Exp Med 209:2351-2365. (IF
13.2)
3. Schlecker E., A. Stojanovic, C. Eisen, C. Quack, C.S. Falk, V. Umansky, A. Cerwenka. 2012.
Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent
recruitment of regulatory T cells favouring tumor growth. J.Immunol 189:5602-5611. (IF 5.5)
4. Textor S., N. Fiegler, A. Arnold, A. Porgador, T.G. Hofmann, A. Cerwenka. 2011. Human NK
cells are alerted to induction of p53 in cancer cells by up-regulation of the NKG2D-ligands
ULBP1 and ULBP2. Cancer Res 71:5998-6009. (IF 8.7)
5. Nausch N., I.E. Galani, E. Schlecker, A. Cerwenka. 2008. Mononuclear Myeloid-Derived
“Suppressor” Cells express RAE-1 and activate NK cells. Blood 112:4080-9. (IF 9.1)
6. Wendel M., I.E. Galani, E. Suri-Payer, A. Cerwenka. 2008. NK cell accumulation in tumors is
dependent on IFN-g and CXCR3 ligands. Cancer Res. 68:8437-45. (IF 8.7)
7. Cerwenka A., J.L. Baron, L. L. Lanier. 2001. Ectopic expression of retinoic acid early inducible1 gene (RAE-1) permits NK cell-mediated rejection of a MHC class I-bearing tumor in vivo.
Proc Natl Acad Sci USA 98:11521-6. (IF 9.7)
8. Cerwenka A., L.L. Lanier. NK cells, viruses and cancer. 2001. Nat Immunol Rev 1:41-49. (IF
33.1)
APPENDIX I
9. Cerwenka A., A.B.H. Bakker, T. McClanahan, J. Wagner, J. Wu, J.H. Phillips, L.L. Lanier.
2000. Retinoic acid early inducible genes define a ligand family for the activating NKG2D
receptor in mice. Immunity 12:721-727. (IF 19.8)
55
PROF. DR. ALEXANDER H. ENK
1. Gebhardt C., A. Riehl, M. Durchdewald, J. Németh, G. Fürstenberger, K. Müller-Decker, A.H.
Enk, B. Arnold, A. Bierhaus, P. Nawroth, J. Hess, P. Angel. 2008. RAGE signaling sustains
inflammation and promotes tumor development. J Exp Med 205:275-285. (IF 13,21)
2. Jonuleit H., E. Schmitt, H. Kakirman, M. Stassen, J. Knop, A.H. Enk. 2002. Infectious
tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional
CD4(+) T helper cells. J Exp Med 196:255-60. (IF 13,21)
3. Jonuleit H., E. Schmitt, M. Stassen, A. Tuettenberg, J. Knop, A.H. Enk. 2001. Identification and
functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated
from peripheral blood. J Exp Med 193:1285-94. (IF 13,21)
4. Lonsdorf A.S., S.T. Hwang, A.H. Enk. 2009. Chemokine receptors in T-cell-mediated diseases
of the skin. J Invest Dermatol 129:2552-66. (IF 6,19)
5. Mahnke K, Y. Qian, S. Fondel, J. Brueck, C. Becker, A.H. Enk. 2005. Targeting of antigens to
activated dendritic cells in vivo cures metastatic melanoma in mice. Cancer Res 65:7007-12.
(IF 8,65)
6. Mahnke K., Y. Qian, J Knop, A.H. Enk. 2003. Dendritic cells, engineered to secrete a T-cell
receptor mimic peptide, induce antigen-specific immunosuppression in vivo. Nat Biotechnol
21:903-8. (IF 32,43)
7. Mahnke K., Y. Qian, J. Knop, A.H. Enk. 2003. Induction of CD4+/CD25+ regulatory T cells by
targeting of antigens to immature dendritic cells. Blood 101:4862-9. (IF 9,06)
8. Steinbrink K., E. Graulich, S. Kubsch, J. Knop, A.H. Enk. 2002. CD4(+) and CD8(+) anergic T
cells induced by interleukin-10-treated human dendritic cells display antigen-specific
suppressor activity. Blood 99:2468-76. (IF 9,06)
APPENDIX I
9. Steinbrink K., H. Jonuleit, G. Müller, G. Schuler, J. Knop, A.H. Enk. 1999. Interleukin-10treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells
resulting in a failure to lyse tumor cells. Blood 93:1634-42. (IF 9,06)
56
DR. MORITZ FELCHT
1. Felcht M., R. Luck, A. Schering, P. Seidel, K. Srivastava, J. Hu, A. Bartol, Y., Kienast, C.
Vettel, E.K. Loos, S. Kutschera, S. Bartels, S. Appak, E. Besemfelder, D. Terhardt, E.
Chavakis, T. Wieland, C. Klein, M. Thomas, A. Uemura, S. Goerdt, H.G. Augustin. 2012.
Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin
Invest 122:1991-2005. (IF 12,81)
APPENDIX I
2. Thomas M.*, M. Felcht*, K. Kruse, S. Kretschmer, C. Deppermann, A.V. Benest, U. Fiedler,
H.G. Augustin. 2010. Angiopoietin-2 stimulation of endothelial cells induces alphavbeta3
integrin internalization and degradation. J Biol Chem 285:23842-9. (IF 4,65); *equal
contribution
57
PD DR. CYRILL GÉRAUD
1. Bioulac-Sage P., S. Lepreux, K. Schledzewski, G. Cubel, C. Géraud, S. Goerdt, C. Balabaud.
2010. Identification of liver sinusoidal endothelial cells in the human liver. Liver Int 30:773-6. (IF
3.87)
2. Evdokimov K., S. Biswas, M. Adrian, J. Weber, K. Schledzewski, M. Winkler, S. Goerdt, C.
Géraud. 2013. Proteolytic cleavage of LEDA-1/PIANP by furin-like proprotein convertases
precedes its plasma membrane localization. Biochem Biophys Res Commun 434: 22-27. (IF
2.40)
3. Géraud C., C. Mogler, A. Runge, K. Evdokimov, S. Lu, K. Schledzewski, B. Arnold, G.
Hämmerling, P.S. Koch, K. Breuhahn, T. Longerich, A. Marx, C. Weiss, F. Damm, A. Schmieder,
P. Schirmacher, H.G. Augustin, S. Goerdt. 2013. Endothelial transdifferentiation in
hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with
increased survival. Liver Int 33:1428-40. (IF 3.87)
4. Géraud C.*, K. Evdokimov*, B.K. Straub, W.K. Peitsch, A. Demory, Y. Dorflinger, K.
Schledzewski, A. Schmieder, P. Schemmer, H.G. Augustin, P. Schirmacher, S. Goerdt. 2012.
Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver
sinusoids. PLoS One 7:e34206. (* C.G. and E.K. contributed equally to this work) (IF 3.73)
5. Géraud C.*, K. Schledzewski*, A. Demory, D. Klein, M. Kaus, F. Peyre, C. Sticht, K.
Evdokimov, S. Lu, A. Schmieder, S. Goerdt. 2010. Liver sinusoidal endothelium: a
microenvironment-dependent differentiation program in rat including the novel junctional
protein liver endothelial differentiation-associated protein-1. Hepatology. 52:313-26. (IF 12.00)
6. Klein D., A. Demory, F. Peyre, J. Kroll, C. Géraud, N. Ohnesorge, K. Schledzewski, B. Arnold,
S. Goerdt. 2009. Wnt2 acts as an angiogenic growth factor for non-sinusoidal endothelial cells
and inhibits expression of stanniocalcin-1. Angiogenesis 12:251-65. (IF 3.97)
APPENDIX I
7. Schledzewski K.*, C. Géraud*, B. Arnold, S. Wang, H.J. Grone, T. Kempf, K.C. Wollert, B.K.
Straub, P. Schirmacher, A. Demory, H. Schonhaber, A. Gratchev, L. Dietz, H.J. Thierse, J.
Kzhyshkowska, S. Goerdt. 2011. Deficiency of liver sinusoidal scavenger receptors stabilin-1
and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious
blood factors. J Clin Invest 121:703-14. (* K.S. and C.G. contributed equally to this work) (IF
12.81)
58
DR. PETER GESERICK
1. Diessenbacher P., M. Hupe, M.R. Sprick, A. Kerstan, P. Geserick, T.L. Haas, T. Wachter, M.
Neumann, H. Walczak, J. Silke, M. Leverkus. 2008. NF-kappaB inhibition reveals differential
mechanisms of TNF versus TRAIL-induced apoptosis upstream or at the level of caspase-8
activation independent of cIAP2. J Invest Dermatol 128:1134-1147. (IF 6,19)
2. Feoktistova M.*, P. Geserick*, D. Panayotova-Dimitrova, M. Leverkus. 2012. Pick your poison:
the Ripoptosome, a cell death platform regulating apoptosis and necrosis. Cell Cycle 11:460-7.
(* equal contribution) (IF 5,24)
3. Feoktistova M.*, P. Geserick*, B. Kellert, D. Panayotova-Dimitrova, C. Langlais, M. Hupe, K.
Cain, M. MacFarlain, G. Häcker, M.Leverkus. 2011. cIAPs block Ripoptosome formation, a
RIP1/caspase 8 containing intracellular cell death complex differentially regulated by cFLIP
isoforms. Mol Cell 43:449-63 (* equal contribution) (IF 15,28)
4. Geserick P., M. Hupe, M. Moulin, M. Leverkus. 2010. RIP-in CD95L-induced cell death: The
control of alternative death receptors pathways by cIAPs. Cell Cycle. 9:2689-2691. (IF 5,24)
5. Geserick P., M. Hupe, M. Moulin, W.W. Wong, M. Feoktistova, B. Kellert, H. Gollnick, J. Silke,
M. Leverkus. 2009. Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1
kinase recruitment. J Cell Biol 187:1037-1054. (IF 10,82)
6. Geserick P., C. Drewniok, M. Hupe, T.L. Haas, P. Diessenbacher, M.R. Sprick, M.P. Schon, F.
Henkler, H. Gollnick, H. Walczak, M. Leverkus. 2008. Suppression of cFLIP is sufficient to
sensitize human melanoma cells to TRAIL or CD95L-mediated apoptosis. Oncogene 27:32113220. (IF 7,36)
8. Leverkus M, P. Diessenbacher, P. Geserick. 2008. FLIPing the coin? Death receptor-mediated
signals during skin tumorigenesis. Exp Dermatol 17:614-622. (IF 3,57)
9. Panayotova-Dimitrova D., M. Feoktistova, M. Ploesser, B. Kellert, M. Hupe, S. Horn, R.
Makarov, F. Jensen, S. Porubsky, A. Schmieder, A.C. Zenclussen, A. Marx, A. Kerstan, P.
Geserick, Y.W. He, M. Leverkus. 2013. cFLIP Regulates Skin Homeostasis and Protects
against TNF-Induced Keratinocyte Apoptosis. Cell Rep 5:397-408. (IF ?)
59
APPENDIX I
7. Kavuri S.M., P. Geserick, D. Berg, D.P. Dimitrova, M. Feoktistova, D. Siegmund, H. Gollnick,
M. Neumann, H. Wajant, M. Leverkus. 2011. Cellular FLICE-inhibitory Protein (cFLIP) Isoforms
Block CD95- and TRAIL Death Receptor-induced Gene Induction Irrespective of Processing of
Caspase-8 or cFLIP inthe Death-inducing Signaling Complex. J Biol Chem 286:16631-16646.
(IF 4,65)
PROF. DR. SERGIJ GOERDT
1. Géraud C., K. Schledzewski, A. Demory, D. Klein, M. Kaus, F. Peyre, C. Sticht, K. Evdokimov,
S. Lu, A. Schmieder, S. Goerdt. 2010. Liver sinusoidal endothelium: a microenvironmentdependent differentiation program in rat including the novel junctional protein liver endothelial
differentiation-associated protein-1. Hepatology 52:313-26. (IF 12.00)
2. Géraud C., K. Evdokimov K, B. K. Straub, W. K. Peitsch, A. Demory, Y. Dörflinger, K.
Schledzewski, A. Schmieder, P. Schemmer, H. G. Augustin, P. Schirmacher, S. Goerdt. 2012.
Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver
sinusoids. PLoS ONE 7:e34206. (IF 3.73)
3. Géraud C., C. Mogler, A. Runge, K. Evdokimov, S. Lu, K. Schledzewski, B. Arnold, G.
Hämmerling, P.S. Koch, K. Breuhahn, T. Longerich, A. Marx, C. Weiss, F. Damm, A. Schmieder,
P. Schirmacher, H.G. Augustin, S. Goerdt. 2013. Endothelial transdifferentiation in
hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with
increased survival. Liver Int 33:1428-40. (IF 3.87)
4. Klein D., A. Demory, F. Peyre, J. Kroll, H.G. Augustin, W. Helfrich, J. Kzhyshkowska, K.
Schledzewski, B. Arnold, S. Goerdt. 2008. Wnt2 acts as a cell type-specific, autocrine growth
factor in rat hepatic sinusoidal endothelial cells cross-stimulating the VEGF pathway.
Hepatolog 47:1018-31. (IF 12.00)
5. Klein D., A. Demory, F. Peyre, J. Kroll, C. Géraud, N. Ohnesorge, K. Schledzewski, B. Arnold,
S. Goerdt. 2009. Wnt2 acts as an angiogenic growth factor for non-sinusoidal endothelial cells
and inhibits expression of stanniocalcin-1. Angiogenesis 12:251-65. (IF 3.97)
6. Kzhyshkowska J., S. Mamidi, A. Gratchev, E. Kremmer, C. Schmuttermaier, L. Krusell, G.
Haus, J. Utikal, K. Schledzewski, J. Scholtze, S. Goerdt. 2006. Novel stabilin-1 interacting
chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and
secreted via lysosomal pathway. Blood 107:3221-8. (IF 9.06)
APPENDIX I
7. Schledzewski K., M. Falkowski, G. Moldenhauer, P. Metharom, J. Kzhyshkowska, R. Ganss, A.
Demory, B. Falkowska-Hansen, H. Kurzen, S. Ugurel, G. Geginat, B. Arnold, S. Goerdt. 2006.
Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+,
F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in
bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J Pathol
209:67-77. (IF 7.58)
8. Schledzewski K., C. Géraud, B. Arnold, S. Wang, H.J. Grone, T. Kempf, K.C. Wollert, B.K.
Kzhyshkowska, S. Goerdt. 2011. Deficiency of liver sinusoidal scavenger receptors stabilin-1
blood factors. J Clin Invest 121:703-14. (IF 12.81)
9. Schmieder A., K. Schledzewski, J. Michel, J.P. Tuckermann, L. Tome, C. Sticht, C. Gkaniatsou,
J.P. Nicolay, A. Demory, J. Faulhaber, J. Kzhyshkowska, C. Géraud, S. Goerdt. 2010.
Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2-like
tumor-associated macrophages expressing the novel CD20 homolog MS4A8A. Int J Cancer
129:122-32 (IF 6.20)
60
PROF. DR. MARTIN LEVERKUS
1. Diessenbacher P., M. Hupe, M.R. Sprick, A. Kerstan, P. Geserick, T.L. Haas, T. Wachter, M.
Neumann, H. Walczak, J. Silke, M. Leverkus. 2008. NF-kappaB inhibition reveals differential
mechanisms of TNF versus TRAIL-induced apoptosis upstream or at the level of caspase-8
activation independent of cIAP2. J Invest Dermatol 128:1134-1147. (IF 6,19)
2. Feoktistova M., P. Geserick, B. Kellert, D.P. Dimitrova, C. Langlais, M. Hupe, K. Cain, M.
Macfarlane, G. Hacker, M. Leverkus. 2011. cIAPs block Ripoptosome formation, a
RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP
isoforms. Mol Cell 43:449-463. (IF 15,28)
3. Geserick P., C. Drewniok, M. Hupe, T.L. Haas, P. Diessenbacher, M.R. Sprick, M.P. Schon, F.
Henkler, H. Gollnick, H. Walczak, M. Leverkus. 2008. Suppression of cFLIP is sufficient to
4. Geserick P., M. Hupe, M. Moulin, W.W. Wong, M. Feoktistova, B. Kellert, H. Gollnick, J. Silke,
M. Leverkus. 2009. Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1
kinase recruitment. J Cell Biol 187:1037-1054. (IF 10,82)
5. Kavuri S.M., P. Geserick, D. Berg, D.P. Dimitrova, M. Feoktistova, D. Siegmund, H. Gollnick,
M. Neumann, H. Wajant, M. Leverkus. 2011. Cellular FLICE-inhibitory Protein (cFLIP)
Isoforms Block CD95- and TRAIL Death Receptor-induced Gene Induction Irrespective of
Processing of Caspase-8 or cFLIP in the Death-inducing Signaling Complex. J Biol Chem
286:16631-16646. (IF 4,65)
6. Leverkus M., M. Neumann, T. Mengling, C.T. Rauch, E.B. Brocker, P.H. Krammer, H.
Walczak. 2000a. Regulation of tumor necrosis factor-related apoptosis-inducing ligand
sensitivity in primary and transformed human keratinocytes. Cancer Res 60:553-559. (IF 8,65)
8. Leverkus M., H. Walczak, A. McLellan, H.W. Fries, G. Terbeck, E.B. Brocker, E.Kampgen.
2000b. Maturation of dendritic cells leads to up-regulation of cellular FLICE- inhibitory protein
and concomitant down-regulation of death ligand- mediated apoptosis. Blood 96:2628-2631.
(IF 9,06)
9. Panayotova-Dimitrova D., M. Feoktistova, M. Ploesser, B. Kellert, M. Hupe, S. Horn, R.
Makarov, F. Jensen, S. Porubsky, A. Schmieder, A.C. Zenclussen, A. Marx, A. Kerstan, P.
Geserick, Y. W.He, M. Leverkus. 2013. cFLIP Regulates Skin Homeostasis and Protects
against TNF-Induced Keratinocyte Apoptosis. Cell Rep 5:397-408. (IF ?)
61
APPENDIX I
7. Leverkus M., M.R. Sprick, T. Wachter, A. Denk, E.B. Brocker, H. Walczak, M. Neumann.
2003. TRAIL-induced apoptosis and gene induction in HaCaT keratinocytes: differential
contribution of TRAIL receptors 1 and 2. J Invest Dermatol 121:149-155. (IF 6,19)
DR. ANKE S. LONSDORF
1. Chien A.J.*, E.C. Moore*, A.S. Lonsdorf, R.M. Kulikauskas, B.G. Rothberg, A. J. Berger, M.B
Major, S.T. Hwang, D. L. Rimm, R. T. Moon. 2009. Activated Wnt/beta-catenin signaling in
melanoma is associated with decreased proliferation in patient tumors and a murine melanoma
model. Proc Natl Acad Sci USA. 106:1193-8. (IF 9.74) *equal contribution, alphabetical order
2. Fang L*, A.S. Lonsdorf*, S.T. Hwang. 2008. Immunotherapy for advanced melanoma. J Invest
Dermatol 128:2596-605. (IF 6,19) * equal contribution, alphabetical order
3. Hedrick M.N.*, A.S. Lonsdorf*, A.K. Shirakawa, C.C. Richard Lee, F. Liao, S.P. Singh, H.H.
Zhang, A. Grinberg, P.E. Love, S.T. Hwang, J.M. Farber. 2009. CCR6 is required for IL-23induced psoriasis-like inflammation in mice. J Clin Invest 119:2317-2329. (IF 12,81) * equal
contribution, alphabetical order
4. Huang V., A.S. Lonsdorf, L. Fang, T. Kakinuma, V.C. Lee, E. Cha, H. Zhang, K. Nagao, M.
Zaleska, W.L. Olszewski, Hwang S.T. 2008. Cutting edge: rapid accumulation of epidermal
CCL27 in skin-draining lymph nodes following topical application of a contact sensitizer recruits
CCR10-expressing T cells. J Immunol 180:6462-6466. (IF 5,52)
5. Kakinuma T., H. Nadiminti, A.S. Lonsdorf, T. Murakami, B.A. Perez, H. Kobayashi, S.T.
Hwang 2007. Small numbers of residual tumor cells at the site of primary inoculation are critical
for anti-tumor immunity following challenge at a secondary location. Cancer Immunol
Immunother 56:1119-31. (IF 3.63)
6. Langer H.F.*, V.V. Orlova*, C. Xie*, S. Kaul*, D. Schneider, A.S. Lonsdorf, M. Fahrleitner,
E.Y. Choi, V. Dutoit, M. Pellegrini, S. Grossklaus, P.P. Nawroth, G. Baretton, S. Santoso, S.T.
Hwang, B. Arnold, T. Chavakis. 2011. A novel function of Junctional Adhesion Molecule-C in
mediating melanoma cell metastasis. Cancer Res 71:4096-4105. (IF 8,65) * equal contribution
APPENDIX I
7. Lonsdorf A.S., B.F. Kraemer, M. Fahrleitner, T. Schoenberger, S. Gnerlich, S. Ring, S.
Gehring, S.W. Schneider, M.J. Kruhlak, S.G. Meuth, B. Nieswandt, M. Gawaz, A.H. Enk, H.F.
Langer. 2012. Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 mediates interaction of melanoma
cells with platelets - a connection to hematogeneous metastasis. J Biol Chem 287:2168-78. (IF
4,65)
8. Lonsdorf A.S., S.T. Hwang, A.H. Enk. 2009. Chemokine receptors in T-cell-mediated diseases
of the skin. J Invest Dermatol 129:2552-2566. (IF 6,19)
9. Lonsdorf A.S., H. Kuekrek, B.V. Stern, B.O. Boehm, P.V. Lehmann, M. Tary Lehmann. 2003.
Intratumor CpG-oligodeoxynucleotide injection induces protective antitumor T cell immunity. J
Immunol 171:3941-3946. (IF 5,52)
62
PROF. DR. KNUT SCHÄKEL
1. Baumeister S.H., K. Holig, M. Bornhauser, M. Meurer, E.P. Rieber, K. Schäkel. 2007. G-CSF
mobilizes slanDCs (6-sulfo LacNAc+ dendritic cells) with a high proinflammatory capacity.
Blood 110:3078-3081. (IF 9,06)
2. Costantini C., F. Calzetti, O. Perbellini, A. Micheletti, C. Scarponi, S. Lonardi, M. Pelletier, K.
Schäkel, G. Pizzolo, F. Facchetti, W. Vermi, C. Albanesi, M.A. Cassatella. 2011. Human
neutrophils interact with both 6-sulfo LacNAc+ DC and NK cells to amplify NK-derived
IFN{gamma}: role of CD18, ICAM-1, and ICAM-3. Blood 117:1677-1686. (IF 9,06)
3. Döbel T., A. Kunze, J. Babatz, K. Tränkner, A. Ludwig, M. Schmitz, A. Enk, K. Schäkel. 2013.
FcγRIII (CD16) equips immature 6-sulfo LacNAc-expressing dendritic cells (slanDCs) with a
unique capacity to handle IgG-complexed antigens. Blood 18:3609-18. (IF 9,06)
4. Hanse A., C. Gunther, J. Ingwersen, J. Starke, M. Schmitz, M. Bachmann, M. Meurer, E.P.
Rieber, K. Schäkel. 2011. Human slan (6-sulfo LacNAc) dendritic cells are inflammatory
dermal dendritic cells in psoriasis and drive strong TH17/TH1 T-cell responses. J Allergy Clin
Immunol 127:787-794. (IF 12,05)
5. Randolph G.J., G. Sanchez-Schmitz, R.M. Liebman, K. Schäkel. 2002. The CD16(+)
(FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells
in a model tissue setting. J Exp Med 196:517-527. (IF 13,22)
6. Schäkel K., R. Kannagi, B. Kniep, Y. Goto, C. Mitsuoka, J. Zwirner, A. Soruri, M. von Kietzell ,
E. Rieber. 2002. 6-Sulfo LacNAc, a novel carbohydrate modification of PSGL-1, defines an
inflammatory type of human dendritic cells. Immunity 17:289-301. (IF 19,80)
8. Schäkel K., M. von Kietzell, A. Hansel, A. Ebling, L. Schulze, M. Haase, C. Semmler, M.
Sarfati, A.N. Barclay, G.J. Randolph, M. Meurer, E.P. Rieber. 2006. Human 6-sulfo LacNAcexpressing dendritic cells are principal producers of early interleukin-12 and are controlled by
erythrocytes. Immunity 24:767-777. (IF 19,80)
9. Schmitz M., S. Zhao, Y. Deuse, K. Schäkel, R. Wehner, H. Wohner, K. Holig, F. Wienforth, A.
Kiessling, M. Bornhauser, A. Temme, M.A. Rieger, B. Weigle, M. Bachmann, E.P. Rieber.
2005. Tumoricidal potential of native blood dendritic cells: direct tumor cell killing and activation
of NK cell-mediated cytotoxicity. J Immunol 174:4127-4134. (IF 5,52)
63
APPENDIX I
7. Schäkel K., E. Mayer, C. Federle, M. Schmitz, G. Riethmuller, E.P. Rieber. 1998. A novel
dendritic cell population in human blood: one-step immunomagnetic isolation by a specific mAb
(M-DC8) and in vitro priming of cytotoxic T lymphocytes. Eur J Immunol 28:4084-4093. (IF
4,97)
DR. ASTRID SCHMIEDER
1. Michel J., K. Schonhaar, K. Schledzewski, C. Gkaniatsou, C. Sticht, B. Kellert, F. Lasitschka,
C. Geraud, S. Goerdt, A. Schmieder. 2013. Identification of the novel differentiation marker
MS4A8B and its murine homolog MS4A8A in colonic epithelial cells lost during neoplastic
transformation in human colon. Cell Death Dis 4:e469. (IF 6.04)
2. Schmieder A., J. Michel, K. Schonhaar, S. Goerdt, K. Schledzewski. 2012a. Differentiation
and gene expression profile of tumor-associated macrophages. Semin Cancer Biol 22:289-97.
(IF 7,44)
3. Schmieder A., K. Schledzewski, J. Michel, K. Schonhaar, Y. Morias, T. Bosschaerts, J. Van
den Bossche, P. Dorny, A. Sauer, C. Sticht, C. Geraud, Z. Waibler, A. Beschin, S. Goerdt.
2012b. The CD20 homolog Ms4a8a integrates pro- and anti-inflammatory signals in novel M2like macrophages and is expressed in parasite infection. Eur J Immunol 42:2971-82. (IF 4.97)
4. Schmieder A., K. Schledzewski, J. Michel, J.P. Tuckermann, L. Tome, C. Sticht, C.
Gkaniatsou, J.P. Nicolay, A. Demory, J. Faulhaber, J. Kzhyshkowska, C. Geraud, S. Goerdt.
2011. Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of
M2-like tumor-associated macrophages expressing the novel CD20 homolog MS4A8A. Int J
Cancer 129:122-32. (IF 6.20)
5. Schoenhaar K, Schledzewski K, Michel J, Dollt C, Gkaniatsou C, Géraud C, Kzhyshkowska J,
Goerdt S, Schmieder A. 2013. Expression of Stabilin-1 in M2 macrophages in human
granulomatous disease and melanocytic lesions. Int J Clin Exper Pathol, in press. (IF 2.2)
APPENDIX I
64
PROF. DR. STEFAN W. SCHNEIDER
1. Bauer A.T, E.A. Strozyk, C. Gorzelanny, C. Westerhausen, A. Desch, M.F. Schneider, S. W.
Schneider. 2011. Cytotoxicity of silica nanoparticles through exocytosis of von Willebrand
factor and necrotic cell death in primary human endothelial cells. Biomaterials 32:8385-93. (IF
7,60)
2. Chen H., M.A. Fallah, V. Huck, J.I. Angerer, A.J. Reininger, S.W. Schneider, M.F. Schneider,
A. Alexander-Katz. 2013. Blood-clotting-inspired reversible polymer-colloid composite
assembly in flow. Nat Commun 4:1333. (IF 10,02)
3. Desch A., E.A. Strozyk, A.T. Bauer, V. Niemeyer, T. Wieland, S.W. Schneider. 2012. Highly
invasive melanoma cells activate the vascular endothelium via a MMP-2/ integrin ανβ5-induced
secretion of VEGF-A. Am J Pathology 181:693-705. (IF 4.51)
4. Görge T., A. Barg, E.M. Schnäker, B. Pöppelmann, V. Shpacovitch, A. Rattenholl, T.A. Luger,
M. Steinhoff, S.W. Schneider. 2006. Melanoma-derived MMP-1 targets endothelial PAR1
promoting endothelial cell activation. Cancer Res 66:7766-74. (IF 8,65)
5. Kerk N., E.A. Strozyk, B. Pöppelmann, S.W. Schneider. 2010. The mechanism of melanomaassociated thrombin activity and von Willebrand factor release from endothelial cells. J Invest
Dermatol 130:2259-68. (IF 6,19)
6. Pappelbaum K.I., C. Gorzelanny, S. Grässle, J. Suckau M.W. Laschke, M. Bischoff, C. Bauer,
M. Schorpp-Kistner, C. Weidenmaier, R. Schneppenheim, T. Obser, B. Sinha, S.W.
Schneider. 2013. Ultra-large von Willebrand factor fibers mediate luminal Staphylococcus
aureus adhesion to an intact endothelial cell layer under shear stress. Circulation 128:50-59.
(IF 15,20)
8. Schneider S. W., S. Nuschele, A. Wixforth, A. Alexander-Katz, R.R. Netz, C. Gorzelanny, M.F.
Schneider. 2007. Shear-induced unfolding triggers adhesion of VWF fibers. Pro. Natl Acad Sci
USA 104:7899-903. (IF 9,74)
9. Steinhoff M., A. Steinhoff, B. Homey, T.A. Luger, S.W.Schneider. 2006. Role of vasculature in
atopic dermatitis. J Allergy Clin Immunol. 118:190-7. (IF 12,05)
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APPENDIX I
7. Riehemann K, S.W. Schneider, T.A. Luger, B. Godin, M. Ferrari, H. Fuchs. 2009.
Nanomedicine: challenge and perspectives. Angewandte Chemie Int. edition 48:872-97. (IF
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PROF. DR. JONATHAN SLEEMAN
1. Baumann P., N. Cremers, F. Kroese, G. Orend, R. Chiquet-Ehrismann, T. Uede, H. Yagita, J.
P. Sleeman. 2005. CD24 expression causes the acquisition of multiple cellular properties
associated with tumor growth and metastasis. Cancer Res 65:10783-10793. (IF 8.65)
2. Baumann P., W. Thiele, N. Cremers, S. Muppala, J. Krachulec, M. Diefenbacher, O. Kassel, G.
Mudduluru, H. Allgayer, M. Frame, J.P. Sleeman. 2012. CD24 interacts with and promotes the
activity of c-src within lipid rafts in breast cancer cells, thereby increasing integrin-dependent
adhesion. Cell Mol Life Sci, 69:435-448. (IF 5.62)
3. Krishnan J., V. Kirkin, A. Steffen, M. Hegen, D. Weih, S. Tomarev, J. Wilting, J. P. Sleeman.
2003. Differential in vivo and in vitro expression of VEGF-C and VEGF-D in tumors and its
relationship to lymphatic metastasis in immunocompetent rats. Cancer Res 63:713-722. (IF
8.65)
4. Kuch V., C. Schreiber, W. Thiele, V. Umansky, J. P. Sleeman. 2013. Tumor initiating
properties of breast cancer and melanoma cells in vivo are not invariably reflected by spheroid
formation in vitro, but can be increased by long-term culturing as adherent monolayers. Int J
Cancer 132:E94-105. (IF 6.20)
5. Müller T., U. Stein, A. Poletti, L. Garzia, M. Rothley, D. Plaumann, W. Thiele, M. Bauer, A.
Galasso, P. Schlag, M. Pankratz, M. Zollo, J. P. Sleeman. 2010. ASAP1 promotes tumor cell
motility and invasiveness, stimulates metastasis formation in vivo, and correlates with poor
survival in colorectal cancer patients. Oncogene 29:2393-2403. (IF 7.36)
6. Neeb A., S. Wallbaum, N. Novac, I. Scholl, S. Dukovic-Schulze, C. Schreiber, P. Schlag, J.
Moll, U. Stein, J. P. Sleeman. 2012. The immediate early gene Ier2 promotes tumor cell
motility and metastasis, and predicts poor survival of colorectal carcinoma patients. Oncogene
31:3796-806. (IF 7.36)
7. Nestl A., O. Von Stein, K. Zatloukal, W. G. Thies, P. Herrlich, M. Hofmann, J. P. Sleeman.
2001. Gene expression patterns associated with the metastatic phenotype in rodent and
human tumors. Cancer Res. 61:1569-1577. (IF 8.65)
APPENDIX I
8. Schreiber C, V. Kuch, V. Umansky, J. P. Sleeman. 2013. Autochthonous mouse melanoma
and mammary tumors do not express the pluripotency genes Oct4 and Nanog. PLoS One
8:e57465. (IF 3.73)
9. Thiele W., N. Novac, S. Mink, C. Schreiber, D. Plaumann, J. Fritzmann, C. Schwager, T.
Regiert, P. E. Huber, U. Stein, P. Schlag, J. Moll, A. Abdollahi, J.P. Sleeman. 2011. Discovery
of a novel tumor metastasis-promoting gene NVM-1. J Pathol 225:96-105. (IF 7.59)
66
PROF. DR. VIKTOR UMANSKY
1. Jayaraman P., F. Parikh, E. Lopez-Rivera, Y. Hailemichael, A. Clark, G. Ma, D. Cannan, M.
Ramacher, M. Kato, W.W. Overwijk, S.-H. Chen, V. Umansky, A.G. Sikora. 2012. Inducible
nitric oxide synthase (iNOS) controls induction of functional myeloid derived suppressor cells
(MDSC). J Immunol 188:5365-5376. (IF 5.52)
2. Meyer C., A. Sevko, M. Ramacher, A.V. Bazhin, C.S. Falk, W. Osen, I. Borrello, M. Kato, D.
Schadendorf, M. Baniyash, V. Umansky. 2011. Chronic inflammation promotes myeloid
derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma
model. Proc Natl Acad Sci USA 108:17111-17116. (IF 9.74)
3. Schlecker E., A. Stojanovic, C. Eisen, C. Quack, C.S. Falk, V. Umansky, A. Cerwenka, A.
2012. Tumor-Infiltrating Monocytic Myeloid-Derived Suppressor Cells Mediate CCR5Dependent Recruitment of Regulatory T Cells Favoring Tumor Growth. J. Immunol 189:56025611. (IF 5.52)
4. Sevko A., M. Sade-Feldman, J. Kanterman, T. Michels, C.S. Falk, L. Umansky, M. Ramacher,
M. Kato, D. Schadendorf, M. Baniyash, V. Umansky. 2013. Low dose cyclophosphamideenhanced chronic inflammation prevents anti-tumor effects in transgenic mouse melanoma
model. J Invest Dermatol 133:1610-1619. (IF 6.19)
5. Sevko A., T. Michels, M. Vrohlings, L. Umansky, P. Beckhove, M. Kato, G.V. Shurin, M.R.
Shurin, V. Umansky. 2013. Anti-tumor effect of paclitaxel is mediated by inhibition of MDSCs
and chronic inflammation in the spontaneous melanoma model. J Immunol 190:2464-2471. (IF
5.52).
6. Umansky V., O. Abschuetz, W. Osen, M. Ramacher, F. Zhao, M. Kato, D. Schadendorf. 2008.
Melanoma specific memory T cells are functionally active in ret transgenic mice without
macroscopical tumors. Cancer Res 68:9451-9458. (IF 8.65)
8. Zhao F., C. Falk, W. Osen, M. Kato, D. Schadendorf, V. Umansky. 2009. Activation of p38
MAPK Drives Dendritic Cells to Become Tolerogenic in Ret Transgenic Mice Spontaneously
Developing Melanoma. Clin Cancer Res 15:4382-4390. (IF 7.84)
67
APPENDIX I
7. Umansky V., A. Sevko. 2012. Melanoma-induced immunosuppression and its neutralization.
Semin. Cancer Biol 22:319-326. (IF 7.44)
PROF. DR. JOCHEN UTIKAL
1. Bernhardt M., E. Orouji, L. Larribere, C. Gebhardt, J. Utikal. 2014. Efficacy of vemurafenib in a
trametinib resistant stage IV melanoma patient. Clin Cancer Res (in press) (IF 7,83)
2. Eminli S*, J. Utikal *, K. Arnold, R. Jaenisch, K. Hochedlinger. 2008. Reprogramming of neural
progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2
expression. . Stem Cells 26:2467-74. * authors contributed equally (IF 7,70)
3. Flaherty K.T., C. Robert, P. Hersey, P. Nathan, C. Garbe, M. Milhem, L.V. Demidov, J.C.
Hassel, P. Rutkowski, P. Mohr, R. Dummer, U. Trefzer, J.M. Larkin, J. Utikal, B. Dreno, M.
Nyakas, M.R. Middleton, J.C. Becker, M. Casey, L.J. Sherman, F.S. Wu, D. Ouellet, A.M.
Martin, K. Patel, D. Schadendorf; the METRIC Study Group. 2012. Improved Survival with MEK
Inhibition in BRAF-Mutated Melanoma. N Engl J Med 367:107-14. (IF 51,65)
4. Hirata A*, J. Utikal *, S. Yamashita, H. Aoki, A. Watanabe, T. Yamamoto, H. Okano, N.
Bardeesy, T. Kunisada, T. Ushijima, A. Hara, R. Jaenisch, K. Hochedlinger, Y. Yamada. 2013.
Dose-dependent roles for canonical Wnt signalling in de novo crypt formation and cell cycle
properties of the colonic epithelium. Development 140:66-75. *authors contributed equally (IF
6,20)
5. Maherali N., T. Ahfeldt, A. Rigamonte, J. Utikal, C. Cowen, K. Hochedlinger. 2008. A highefficiency system for the generation and study of human induced pluripotent stem cells. Cell
Stem Cell 3:340-5. (IF 25,31)
6. Maherali N, R. Sridharan, W. Xie, J. Utikal, S. Eminli, K. Arnold, M. Stadtfeld, R. Yachechko, J.
Tchieu, R. Jaenisch, K. Plath, K. Hochedlinger. 2007. Directly reprogrammed fibroblasts show
global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1:55-70. (IF
25,31)
7. Stadtfeld M., M. Nagaya, J. Utikal, G. Weir, K. Hochedlinger. 2008. Induced pluripotent stem
cells generated without viral integration. Science 322:945-9. (IF 31,02)
APPENDIX I
8. Utikal J., J.M. Polo, M. Stadtfeld, N. Maherali, W. Kulalert, R.M. Walsh, A. Khalil, J.G.
Rheinwald, K. Hochedlinger. 2009. Immortalization eliminates a roadblock during the
reprogramming of somatic cells into iPS cells. Nature 460:1145-8. (IF 38,59)
9. Utikal J., N. Maherali, W. Kulalert, K. Hochedlinger. 2009. Sox2 is dispensable for the
reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell
Sci 122:3502-10. (IF 5,87)
68
PROF. DR. FRANK WINKLER
1. Egea V, L. von Baumgarten, C. Schichor, B. Berninger, T. Popp, P. Neth, R. Goldbrunner, Y.
Kienast, F. Winkler, M. Jochum, C. Ries. 2011. TNF-alpha respecifies human mesenchymal
stem cells to a neural fate and promotes migration toward experimental glioma. Cell Death
Differ 18:853-63. (IF 8.8)
2. Garkavtsev I., S.V. Kozin, O. Chernova, L. Xu, F. Winkler, E. Brown, G.H. Barnett, R.K. Jain.
2004. The candidate tumour suppressor protein ING4 regulates brain tumour growth and
angiogenesis. Nature 428:328-32. (IF 36.3)
3. Kienast Y., L. von Baumgarten, M. Fuhrmann, W. Klinkert, R. Goldbrunner, J. Herms, F.
Winkler. 2010. Real-time imaging reveals the single steps of brain metastasis formation.
Nature Medicine 16:116-122. (IF 22.5)
4. Tong R.T., Y. Boucher, S.V. Kozin, F. Winkler, D.J. Hicklin, R.K. Jain. 2004. Vascular
normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure
gradient across the vasculature and improves drug penetration in tumors. Cancer Res
64:3731-6. (IF 7.9)
5. von Baumgarten L., D. Brucker, A. Tirniceru, Y. Kienast, S. Grau, S. Burgold, J. Herms, F.
Winkler. 2011. Bevacizumab has differential and dose-dependent effects on glioma blood
vessels and tumor cells. Clin Cancer Res 17:6192-205. (IF 7.7)
6. Winkler F., Y. Kienast, M. Fuhrmann, L. von Baumgarten, S. Burgold, G. Mitteregger, J.
Herms. 2009. Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and
peritumoral angiogenesis. Glia 57:1306-15. (IF 4.8)
8. Xu L., D. M. Cochran, R. T. Tong, F. Winkler, S. Kashiwagi, R. K. Jain, D. Fukumura. 2006.
Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by
depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer
Res 66:3971-3977. (IF 7.9)
69
APPENDIX I
7. Winkler F., S.V. Kozin, R.T. Tong, S. Chae, M.F. Booth, I. Garkavtsev, L. Xu, D.K. Hicklin, D.
Fukumura, E. di Tomaso, L.L. Munn, R.K. Jain. 2004. Kinetics of vascular normalization by
VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation,
Angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553-563. (IF 26.6)
Appendix II
1
Biographical Sketches of the Participating Researchers
PROF. DR. RER. NAT. PETER ANGEL
Head of Division
Signal Transduction and Growth Control (A100)
German Cancer Research Center (DKFZ)
Im Neuenheimer Feld 280
69120 Heidelberg
+49-6221-42-4570 (Fon)
+49-6221-42-4554 (Fax)
[email protected]
Curriculum vitae
1995 - to date
1990 - 1995
1987 - 1989
1993 - 1987
1982 - 1993
Head of Division "Signal Transduction and Growth Control" at the
German Cancer Research Center (DKFZ), Heidelberg
Head of Research Group at the Institute of Genetics, Research
Center Karlsruhe
Postdoctoral Fellow at the University of California San Diego
PhD Study at the University Karlsuhe (summa cum laude)
Diploma at the University Karlsruhe (excellent)
APPENDIX II
Awards and Appointments
January 1990
Young Investor Award (Heisenberg Stipendium) of the German Research
Society (DFG)
November 2003
appointed Full Professor in "Molecular Cell Biology: signal Transduction and
Growth Control" at University Heidelberg
2002 - 2003
Coordinator of Research Program "Tumor Cell Biology" of DKFZ
2003 - 2006
Dep. Coordinator of Res. Program "Cell and Tumor Biology" of DKFZ
2004 - 2012
Elected member of the Study Section "Cell Biology" of the DFG
since 2005
Elected Member of the Board of Trustees (Kuratorium) of the DKFZ
since 2008
Elected EMBO Member
since 2011
Elected member of the Board of Directors of the DKFZ-ZMBH Alliance
since 2012
National Coordinator of the BMBF-funded Program of German-Israeli
Cooperation in Cancer Research
Areas of research expertise
Signal transduction, transcription factors and genetic programs,
communication, genetically modified mouse models, tumor biology
Inflammation,
cell-cell
5 selected (most important) publications
1. Gebhardt C, Riehl A, Durchdewald M, Németh J, Fürstenberger G, Müller-Decker K, Enk A,
Arnold B, Bierhaus A, Nawroth PP, Hess J, Angel P. (2008) RAGE signaling sustaines
inflammation and promotes tumor development; J Exp Med 205:275-85. (IF 13,8)
2. Zenz R, Eferl R, Kenner L, Florin L, Hummerich Mehic D, Scheuch H, Angel P, Tschachler E,
Wagner EF. (2005) Psoriasis-like skin disease and arthritis caused by inducible epidermal
deletion of Jun proteins. Nature 437:369-75. (IF 36,3)
70
3. Szabowski A, Maas-Szabowski N, Andrecht S, Kolbus A, Schorpp-Kistner M, Fusenig NE,
Angel P. (2000) c-Jun and JunB antagonistically control cytokine-regulated mesenchymalepidermal interaction in skin. Cell 103:745-75. (IF 32,4)
4. Angel P, Allegretto EA, Okino ST, Hattori K, Boyle WJ, Hunter T, Karin M. (1988) Oncogene
Jun encodes a sequence specific trans-activator similar to AP1. Nature 332:166-171. (IF 36,3)
5. Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P and Karin
M. (1987) Phorbol ester inducible genes contain a common cis element recognized by a TPA
inducible trans-acting factor. Cell 49:729-739. (IF 32,4)
PhD/MD students (last 5 years) and titles of their theses
PHD
Jurisch-Yaksi, Nathalie (2005 - 09) Positive and negative regulator JunB: impact on chromatin
remodeling and stress response. University Heidelberg. Final degree: magna cum laude
Durchdewald, Moritz (2006 - 09) Identification of the Fos/AP-1-dependent genetic network
implicated in epithelial carcinogenesis. University Heidelberg. Final degree: magna cum laude
Nemeth, Julia: (2005 - 09) Function and regulation of S100 proteins in inflammation-associated
carcinogenesis. University Heidelberg. Final degree: magna cum laude
Riehl, Astrid: (2005 - 09) Identification and characterization of gene regulatory networks controlled
by the receptor RAGE in inflammation and cancer. University Heidelberg, Final degree: summa
cum laude
Hildenbrand, Maike (2006 - 10) Transcriptional regulation of the aspartic protease Taps and its
function during cutaneous wound healing. University Heidelberg. Final degree: magna cum laude
Krenzer, Stefanie (2007 - 10) Regulation and function of the kallikrein-related peptidase 6 in the
development of malignant melanoma. University Heidelberg. Final degree: magna cum laude
Wiechert, Lars (2009 - 12) Function of epithelial-derived S100a8 and S100 a9 proteins in tissue
homeostasis and inflammation in transgenic mouse models. University Heidelberg. Final degree:
magna cum laude
Leibold, Julia (2010-2012: Function of the Receptor for Advanced Glycation End Products in
Keratinocytes in the regulation of skin inflammation. University Heidelberg. Final degree: magna
cum laude
Schumacher, Marion (2010-2013) JNK-dependent dermal genetic program controls interdependent
keratinocyte-fibroblast crosstalk promoting keratinocyte differentiation during cutaneous wound
healing. University Heidelberg. Final degree: magna cum laude
Current extramural funding
DFG Transregio-SFB-77 Leberkrebs von der molekularen Pathogenese zur zielgerichteten
Therapie (2010-2014): TP A07 "Regulation and Function of the S100A8/S100A9 protein
complex in inflammation-associated liver carcinogenesis"
DFG Transregio-SFB-23 "Vaskuläre Differenzierung und Remodellierung" (2013-2017) Teilprojekt
B02 Role of JunB and JunB target genes in endothelial cell function and tumor angiogenesis"
BMBF Programm AGENET (2011-2014): The role of AP-1 subunits in keratinocytes and cells of
the dermal compartment for trans-regulatory mechanisms controlling tissue homeostasis and
remodeling in the skin
DKFZ-Ministry of Science and Technlogy (MOST) of Israel (2011-2014) S100-Rage signalling in
liver tumour angiogenesis
Helmholtz-Gemeinschaft: Pre-clinical Comprehensive Cancer Center (PCCC; 2013-2016) The role
of podoplanin in in vivo mouse models of brain and gastrointestinal tumors
71
APPENDIX II
Kiesow, Kristin (2009-12: miR-182 -anovel Junb target and regulator of lymphangiogenesis in
Danio rerio. University Heidelberg. Final degree: magna cum laude
PROF. DR. MED. VET. HELLMUT G. AUGUSTIN, PHD
Professor and Director
Joint Research Division Vascular Biology,
Medical Faculty Mannheim (CBTM),
Heidelberg University, and
German Cancer Research Center Heidelberg
(DKFZ-ZMBH-Alliance)
Address MA:
Section of Vascular Biology and Tumor Angiogenesis
Center for Biomedicine and Medical Technology (CBTM)
Medical Faculty Mannheim, University of Heidelberg
Ludolf-Krehl-Straße 13-17
68167 Mannheim
0621-383-9962 (Fon)
Address HD:
Dept. of Vascular Oncology and Metastasis
69120 Heidelberg
06221-42-1500 (Fon)
[email protected]
www.angiolab.de
Curriculum vitae
3/2013-pres
Director, Helmholtz Alliance “Preclinical Comprehensive Cancer Center” (PCCC,
www.helmholtz-pccc.de)
APPENDIX II
1/2011-pres.
Deputy Director, Center for Biomedicine and Medical Technology Mannheim
(CBTM), Medical Faculty Mannheim, Heidelberg University, Germany
1/2011-pres.
Director, Center for Molecular Biology and German Cancer Research Center
Alliance (DKFZ-ZMBH-Alliance)
1/2011-pres.
Speaker, Cell and Tumor Biology Research Program (FSP-A), German Cancer
Research Center, Heidelberg, Germany
7/2009-pres.
Speaker of the SFB-TR23 “Vascular Differentiation and Remodeling” of the
Universities Heidelberg and Frankfurt (www.transregio23.de)
5/2006-pres.
Aventis Foundation-endowed Chair for Vascular Biology and Angiogenesis
Research, Joint Research Division Vascular Biology, Medical Faculty Mannheim
(CBTM), Heidelberg University, and German Cancer Research Center Heidelberg
(DKFZ-ZMBH Alliance), Germany
5/2005-pres.
Founding member and elected Chairman of VWFB e.V. (Verein zur Förderung
wissenschaftlicher Fachtagungen e.v.; www.vwfb.de)
5/2005-pres.
Coordinator of the nationwide German tumor-vessel interaction Priority Research
Grant (SPP1190, www.tumorvessel.de)
7/2005-6/2009 Vice Speaker of the SFB-TR23 “Vascular Differentiation and Remodeling” of the
Universities Frankfurt, Heidelberg, and Freiburg (www.transregio23.de)
2002-2006
Adjunct Professor, Medical Faculty of the Albert-Ludwigs-University Freiburg,
Germany
2001-2006
Head, Dept. of Vascular Biology & Angiogenesis Research, Institute of Molecular
Oncology, Tumor Biology Center, Freiburg, Germany (private, non-academic
research institute)
72
9/1998- 5/2006 Coordinator of nationwide German angiogenesis Priority Research Grant
(SPP1069, www.angiogenese.de)
1992-2001
Research Assistant Professor (C1, C2), Clinic for Gynecology and Obstetrics,
University of Göttingen, Germany
Nov. 5, 1997
Venia legendi (Habilitation) in Molecular Cell Biology, University of Göttingen,
Germany
Aug. 24, 1992 PhD, Cornell University, Ithaca, NY, USA
1988-1992
Graduate Student, Dept. of Pathology, Cornell University, Ithaca, NY, USA
Dec. 12, 1987 Doctoral degree Dr. med. vet.
Dec. 3, 1984
License to practice
2/1997
Founder of the German vascular biology network (with biannual meeting
series)
1984-1987
Residency and graduate training in Veterinary Pathology, School of Veterinary
Medicine Hannover, Germany
July 12, 1984
DVM, School of Veterinary Medicine Hannover, Germany
1980-1984
Veterinary Medicine, School of Veterinary Medicine Hannover, Germany
1978-1980
Physikum (B.S.), School of Veterinary Medicine Hannover, Germany
The lab studies 1.) the molecular mechanisms of tumor angiogenesis focusing on angiogenesis
regulating receptor tyrosine kinases, most notably on the Angiopoietin-Tie ligand-receptor system,
2.) the molecular mechanisms of physiological blood and lymphatic vessel formation, assembly,
and maturation focusing on selected novel candidate molecules, 3.) the molecular mechanisms of
tumor progression focusing on tumor-vessel interactions during metastasis (role of tumor cell –
endothelial cell interactions in the control of site-specific metastasis), and 4.) translational tumor
angiogenesis experiments aimed at defining the therapeutic window of anti-angiogenic tumor
therapies. Conceptually, the lab’s work is considered as basic tumor biology research with the aim
of identifying and validating novel therapeutic targets.
Hu, J., Srivastava, K., Wieland, M., Runge, A., Mogler, C., Besemfelder, E., Terhardt, D., Vogel, M.
J., Cao, L., Korn, C., Bartels, S., Thomas, M., and Augustin, H. G. (2014) Endothelial cell-derived
Angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science, 343: 416-9, 2014
(IF 31,03)
Felcht, M., R. Luck, A. Schering, P. Seidel, K. Srivastava, J. Hu, A. Bartol, Y., Kienast, C. Vettel,
Wieland, C. Klein, M. Thomas, A. Uemura, S. Goerdt, and H.G. Augustin. (2012) Angiopoietin-2
differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest. 122:19912005 (IF 12,81)
Helfrich, I., Scheffrahn, I., Bartling, S., Weis, J., von Felbert, V., Middleton, M., Kato, M., Ergün, S.,
Augustin, H. G.*, Schadendorf, D.* (2010) Resistance to antiangiogenic therapy is directed by
vascular phenotype, vessel stabilization, and maturation in malignant melanoma. J Exp Med. 207:
491-503 (*equally contributing senior authors) (IF 13,21)
Alajati, A., A.M. Laib, H. Weber, A.M. Boos, A. Bartol, K. Ikenberg, T. Korff, H. Zentgraf, C.
Obodozie, R. Graeser, S. Christian, G. Finkenzeller, G.B. Stark, M. Héroult, and H.G. Augustin.
2008. Spheroid-based engineering of a human vasculature in mice. Nat Methods, 5: 439-45. (IF
23,57)
Fiedler, U., Y. Reiss, M. Scharpfenecker, V. Grunow, S. Koidl, G. Thurston, N.W. Gale, M.
Witzenrath, S. Rosseau, N. Suttorp, A. Sobke, M. Herrmann, K. Preissner, P. Vajkoczy, and H.G.
Augustin. 2006. Angiopoietin-2 sensitizes endothelial cells to TNFα and plays a crucial role in the
induction of inflammation. Nature Med. 12:235-9. (IF 24,30)
73
APPENDIX II
PhD students (last 5 years) and titles of their theses
Markus Thomas, Molecular mechanisms of angiopoietin-2-mediated destabilization of the vascular
endothelium, 2008.
Karoline Kruse, Regulation der vaskulären Homöostase durch den Tie2 Liganden Angiopoietin-2 und
Nitritoxid, 2008.
Renate Becker, Molecular analysis of Endosialin and its interaction with Mac-2 Binding protein, 2009.
Daniel Epting, Analysis of G-protein signaling molecules during vertebrate development and
angiogenesis, 2009.
Silke Kaltenthaler, Identification of CD36 as a novel regulator of lymphatic endothelial cell function,
2009.
Anna Laib, Establishment of a novel human in vivo lymphangiogenesis assay based on the use of
endothelial cell spheroids, 2010.
Simone Kutschera, Functions of Semaphorin 3G during angiogenesis, lymphangiogenesis and tumor
development, 2010.
Joycelyn Wüstehube, Characterization of cerebral cavernous malformation protein CCM1 in
endothelial cells, 2011.
Christian Dietz, Analyses of small Rho-GTPases signaling molecules during vertebrate development
and angiogenesis, 2011.
Arne Bartol, The role of the Angiopoietin-Tie system in blood vessel maturation and maintance, 2012.
Anja Weick, Identification of Semaphorin 3G as a novel regulator of tumor lymphangiogenesis and
metastasis, 2013.
Matthias Wieland, Role of hepatic stellate cell-expressed endosialin in liver health and disease, 2013.
Sonija Savant, The role of Tie1 receptor in Angiopoietin-Tie2 signaling during vascular
morphogenesis, 2013.
German Research Council: Vascular differentiation and Remodeling; Speaker project within
SFB/TR 23 (2009-2017).
German Research Council: Role of the Angiopoietin/Tie2 system in controlling vascular
morphogenesis and homeostasis; project within the SFB-TR23 (2005-2017).
APPENDIX II
EU FP7 Project SyStemAge: “Systems Biology of Stem Cell Ageing” (2013-2017).
Helmholtz Alliance: Preclinical Comprehensive Cancer Center” (2013-2016).
Leducq Foundation Transatlantic Network of Excellence: Lymph vessels in obesity and
cardiovascular research (2012-2016).
German Research Council: Tumor-specific vascular reprogramming in HCC; project within the
SFB-TR77 (2010 - 2014).
German Research Council: The role of Angiopoietin/Tie system in regulating the stem cell niche;
SFB873 (2010-2014).
74
DR. IRIS AUGUSTIN
Div. Signaling and Functional Genomics
DKFZ and University Heidelberg
D-69120 Heidelberg
06221 421955 (Fax)
06221 421959 (Fax)
[email protected]
Curriculum vitae
since 2008
2004-2008
2002-2004
2001-2002
1998-2000
1999
1995-1998
1991-1995
1989-1991
Senior Scientist, DKFZ & Heidelberg Univ., Heidelberg
Maternaty leave (third child)
Postdoctoral Fellow, MPI for Immunology, Freiburg
Maternaty leave (second child)
Postdoctoral Fellow, MPI for experimental Medicine, Göttingen
Otto-Hahn-Medaille of MPG
PhD, MPI for experimental Medicine, Göttingen
Biology, University Göttingen
Biology, University Cologne
since 2008 Wnt signaling in skin development, embryonic stem cells and tumors
2002-2004 Function of Protocaherins in brain architecture
1995-2000 Neurotransmitter release at synapses
Augustin, I, Gross J, Baumann D, Korn C, Kerr G, Grigoryan T, Mauch C, Birchmeier W, Boutros
M, 2013 Psoriasiform dermatitis-related phenotype caused by loss of epidermal Wnt secretion. J.
Exp. Med. 26:1761-77. (IF 13,21)
Augustin, I., V. Goidts, A. Bongers, G. Kerr, G. Vollert, B. Radlwimmer, C. Hartmann, C. HeroldMende, G. Reifenberger, A. von Deimling, and M. Boutros. 2012. The Wnt secretion protein
Evi/Gpr177 promotes glioma tumourigenesis. EMBO molecular medicine 4:38-51. (IF 7,80)
Augustin, I., S. Korte, M. Rickmann, H.A. Kretzschmar, T.C. Sudhof, J.W. Herms, and N. Brose.
2001. The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic
transmission and motor learning in mice. The Journal of neuroscience: The official journal of the
Society for Neuroscience 21:10-17. (IF 6,91)
Augustin, I., C. Rosenmund, T.C. Sudhof, and N. Brose. 1999b. Munc13-1 is essential for fusion
competence of glutamatergic synaptic vesicles. Nature 400:457-461. (IF 38.60)
75
APPENDIX II
Korn C, Scholz B, Hu J, Srivastava K, Wojtarowicz J, Arnsperger T, Adams R, Boutros M, Augustin
HG, Augustin I (2014) Endothelial cell derived non-canonical Wnt ligands control vascular pruning
in developmental angiogenesis. Development in press (IF 6,9)
Claudia Korn (2001-2014)
Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis
Master students and titles of their theses
Dyah Dewi (01/2013 – 09/2013)
Analysis of Evi in embryonic stem cells and teratoma
Daniel Baumann (02/2012 – 09/2012)
Functional analysis of Evi in epithelial knockout mice
Gordon Vollert (09/2010 – 06/2011)
Functional analysis of Evi in transgenic embryonic stem cells and mice
Nesrin Tuysuz (10/2009 – 04/2010)
Generation and characterization of Evi-transgenic embryonic stem cells
APPENDIX II
76
PROF. DR. RER. NAT. MICHAEL BOUTROS
Division Signaling and Functional Genomics
69120 Heidelberg, Germany
Department Cell and Molecular Biology
Medical Faculty Mannheim
+49-(0) 6221-42-1951 (Phone)
+49-(0) 6221-42 1959 (Fax)
[email protected]
Curriculum vitae
2008 – to date
2008 – to date
2003 – 08
1999 – 03
1999 – 01
1996 – 99
1995 – 96
1994 – 95
1993 – 96
1991 – 93
Head of Division, German Cancer Research Center (DKFZ)
Professor and Chair, Cell and Molecular Biology, University of Heidelberg,
Medical Faculty Mannheim
Independent Group leader, German Cancer Research Center (DKFZ)
Heidelberg, Germany.
Postdoctoral fellow, Harvard Medical School, USA
M.P.A., Kennedy School of Government, Harvard University, USA
Ph.D., European Molecular Biology Laboratory and
Heidelberg University, Heidelberg
Diploma thesis research, Cold Spring Harbor Laboratory, USA
Fulbright Exchange Program, SUNY Stony Brook, USA
Studies in Biochemistry, University Witten/Herdecke
Studies in Biology, RWTH Aachen
Augustin, I., Gross, J., Baumann, D., Korn, C., Kerr, G., Grigoryan, T., Mauch, C., Birchmeier, W.,
and M. Boutros. 2013. Loss of epidermal Evi/Wls results in a phenotype resembling psoriasiform
dermatitis. Journal of Experimental Medicine 210:1761-77. (IF 13.21)
Gross, J.C., V. Chaudhary, K. Bartscherer, and M. Boutros. 2012. Active Wnt proteins are
secreted on exosomes. Nat Cell Biol. 14:1036–1045. (IF 20.76)
Bartscherer, K., N. Pelte, D. Ingelfinger, and M. Boutros. 2006. Secretion of Wnt Ligands requires
Evi, a conserved transmembrane protein. Cell 125:523-533. (IF 31.96)
Boutros, M., A.A. Kiger, S. Armknecht, K. Kerr, M. Hild, B. Koch, S.A. Haas, R. Paro, and N.
Perrimon. 2004. Genome-wide RNAi analysis of growth and viability in Drosophila cells. Science
303:832-835. (IF 31.03)
Boutros M., N. Paricio, D. Strutt, and M. Mlodzik. 1998. Dishevelled activates JNK and
discriminates between JNK pathways in planar polarity and wingless signaling. Cell 94:109-18. (IF
31.96)
77
APPENDIX II
Wnt signaling in development and cancer, systems genetics and synthetic lethality,
high-throughput screening and high-throughput imaging
Kubilay Demir, Identification and functional analysis of RAB8B as a regulator of WNT/beta-Catenin
signaling pathway, 2007 – 2012, magna cum laude
Thomas Horn, Mapping of signaling networks through synthetic genetic interaction analysis by RNAi,
2007 – 2010, summa cum laude
Tina Buechling, Characterization of novel mediators of the Wnt/Frizzled signal transduction cascade,
2006 – 2010, summa cum laude
Dorothee Nickles, Identification of Novel Regulators of TNF-α Signaling using Genome-wide RNAi
Screens, 2006 – 2010, magna cum laude
Zeynep Arziman, Systematic analysis of RNAi experiments and deep sequencing data, 2004 – 2008,
magna cum laude
Sandra Steinbrink, Identification of modifiers of cellular viability and TRAIL-induced apoptosis using
genome-wide RNAi screens, 2004- 2008, magna cum laude
Kerstin Bartscherer, Identification and characterization of Evi, a novel regulator of Wnt secretion, 2004
– 2007, summa cum laude
David Kuttenkeuler, Dissection of Nuclear Factor kB Pathways in Drosophila Innate Immunity, 2003 –
2007, magna cum laude
Viola Gesellchen, Identification of new modifiers of the Imd immune signaling pathway, 2003 – 2007,
magna cum laude
ERC Advanced Grant, Synthetic Genetic Interaction Analysis, 2012-2017, PI
Hartmut-Hoffmann Berling International Graduate School for Molecular and Cellular Biology
(HBIGS), Excellence Initiative (DFG/BMBF), Principal Investigator and Member Executive Board
(2007-2012)
APPENDIX II
Excellence Cluster CellNetworks, 2010-2012, DFG, Principal Investigator and Member of the
Steering Committee
Forschergruppe Wnt FOR1036, Mechanisms, functions and evolution of Wnt signaling pathways,
2012-2014, DFG, BO1791/4-2, PI
Collaborative Research Center 873, Maintenance and Differentiation of Stem Cells in Development
and Disease, DFG, 2010-2014, PI
78
PD DR. ADELHEID CERWENKA
German Cancer Research Center
Boveri Junior Research Group/DKFZ/D080
D-69120 Heidelberg
Phone: +49 6221 42 4480 Fax: +49 6221 42 3759
[email protected]
Curriculum vitae
2007
Venia Legendi for Immunology, University of Heidelberg,
Faculty of Medicine, Heidelberg, Germany
2003 - today Head of Boveri Junior Group “Innate Immunity” at the German Cancer Research
Center, Heidelberg, German
2001 - 2003 Head of Laboratory, Division of Autoimmune Diseases, Novartis Research Institute,
Vienna, Austria
1998 - 2001 Post-doc, DNAX Research Institute and University of California, San Francisco,
USA, with Prof. Lewis L. Lanier
1996 - 1998 Post-doc, University of California, San Diego, CA, USA and at the Trudeau Institute,
NY, USA, with Prof. Richard W. Dutton
1991 - 1995 PhD, Institute of Immunology, University of Vienna, with Prof. Walter Knapp
1986 - 1991 Diploma in Pharmacy, Institute of Immunology, University of Vienna, Austria
1986
Abitur, Piaristengymnasium Krems, Austria, Golden Ring Award “summa cum laude”
Fiegler N, Textor S, Arnold A, Rölle A, Oehme I, Breuhahn K, Moldenhauer G, Witzens-Harig M,
Cerwenka A. 2013. Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors
impairs tumor cell recognition by NK cells, Blood, Aug 1;122(5):684-93. (IF 9.0)
J. Ni, M. Miller, A. Stojanovic, N. Garbi, A. Cerwenka. 2012. Sustained effector function of IL12/15/18 preactivated NK cells against established tumors” J Exp Med 209(13):2351-65. (IF 13.2)
APPENDIX II
Tumor immunity, Innate immunity, Natural Killer cells
Textor S, Fiegler N, Arnold A, Porgador A, Hofmann TG, Cerwenka A. 2011. Human NK cells are
alerted to induction of p53 in cancer cells by up-regulation of the NKG2D-ligands ULBP1 and ULBP2,
Cancer Res. 71(18):5998-6009. (IF 8.6)
N. Nausch, I. E Galani, E. Schlecker and A. Cerwenka 2008. Mononuclear Myeloid-Derived
“Suppressor” Cells express RAE-1 and activate NK cells. Blood 112(10):4080-9. (IF 9.0)
A. Cerwenka, A. B. H. Bakker, T. McClanahan, J. Wagner, J. Wu, J. H. Phillips, and L. L. Lanier
2000. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor
in mice (2000). Immunity. 12: 721-727. (IF 19.8)
79
PhD
Anja Tessarz, 2007, Identifying key players in TREM-1/DAP12 signalling
Sonja Textor, 2008, Role of NK cells and NK cell receptor ligands in cervical carcinogenesis
Kai Zanzinger, 2008, Expression and signalling of triggering receptor expressed on myeloid cells
(TREM)-1
Norman Nausch, 2008, The importance of NKG2D-RAE-1 in anti-tumor immune response
Ioanna Evdokia Galani, 2008, Enhancing anti-tumor immunity to MHC class-I-deficient tumors: role
of regulatory T cells and type I IFN
Marco Wendel, 2009, Mechanism of natural killer cell accumulation in tumors
Ana Stojanovic, 2009, Molecular signature of tumor-infiltrating NK cells
Eva Schlecker, 2011, The role of tumor-infiltrating MDSC subsets in tumor progression
Nathalie Fiegler, 2013, Expression, regulation, and function of the Natural Killer Cell ligand B7-H6 in
tumor cells
German Carreras Foundation, Deutsche Carreras Stiftung Leukämie-Stiftung e.V: DJCLS R
11/06: Activation of Natural Killer cells by NKp30/B7-H6 in haematological neoplasia, 2011-2014
Joint Project: DKFZ-Bayer Health Care, 2011-2014
APPENDIX II
Joint Project: DKFZ-Karolinska Institute, Role of Natural Killer cells in hepatocellular cancer (HCC)
pathogenesis, 2012-2014
German Cancer Aid, Deutsche Krebshilfe, 110442, Generation of human CD8+ T lymphocytes
co-expressing antigen-specific T cell receptors and activating NK cell receptors for immunotherapy
of cancer, 2013-2016
80
PROF. DR. MED. ALEXANDER H. ENK
Curriculum vitae
2004-to date
1997
1995
1993
1993
1992-1994
1990-1992
1988-1990
1988
1988
1984-1988
1983 – 1988
1982 – 1988
Appointment as Chairman and Full Professor, Dept. of Dermatology and
Venerology, Ruprecht-Karls-University of Heidelberg
Associate Professor and Vice Chairman, Dept. of Dermatol, JohannesGutenberg University of Mainz
Venia legendi for Dermatology and Venerology, Johannes-Gutenberg
University of Mainz, “Frühe molekulare Veränderungen in der
Induktionsphase der allergischen Kontaktdermatitis”1994-1997 Assistant
Professor, Dept. of Dermatol., Johannes-Gutenberg University of Mainz
Board Certification Allergology
Board Certification Dermatology and Venerology
Resident Dept. of Dermatol., Johannes-Gutenberg the University of
Mainz1992
Forgarty Scholarship of the National Institutes of Health (NIH)
Postdoctoral Fellowship, Dermatol. Branch of the National Institutes of
Health (NIH), DFG scholarship
“Arzt im Praktikum”, Dept. of Dermatol. Johannes-Gutenberg University of
Mainz
Fullbright Scholarship
“Arzt im Praktikum”, Dept. of Dermatol., University Hospital Münster
Promotion to Dr. med. , Dept. of Dermatol. of the University of Münster),
Thesis: “Produktion von IFN-γ durch epidermale LC nach Stimulation”
Scholarship of the Studienstiftung des Deutschen Volkes (German Research
Foundation)
Medical School, Westf. Wilhelms-Universität Münster
Dermato-Oncology, Contact Hypersensitivity, Inflammation, Immunology
Mahnke K., Qian Y., Fondel S., Brueck J., Becker C. and A.H. Enk. 2005. Targeting of antigens to
activated dendritic cells in vivo cures metastatic melanoma in mice. Cancer Res. 1;65(15): 700712. (IF 8,65)
Mahnke K., Qian Y. Knop J., and A.H. Enk .2003. Dendritic cells, engineered to secrete a T-cell
receptor mimic peptide, induce antigen-specific immunosuppression in vivo. Nat Biotechnol.
21(8):903-8. (IF 32,43)
Mahnke K., Qian Y., Knop J. and A.H. Enk. 2003. Induction of CD4+/CD25+ regulatory T cells by
targeting of antigens to immature dendritic cells. Blood 15;101(12):4862-9. (IF 9,06)
81
APPENDIX II
Chairman and Full Professor
Department of Dermatology
University Medical Center Heidelberg,
Ruprecht-Karls-University of Heidelberg
Voßstrasse 2
69115 Heidelberg
06221 56 8501 (Fon)
06221 56 5406 (Fax)
[email protected]
Jonuleit H., Schmitt E., Kakirman H., Stassen M., Knop J. and A.H. Enk. 2002.Infectious tolerance:
human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper
cells. J Exp Med.15;196(2):255-60. (IF 13,21)
Jonuleit H., Schmitt E., Stassen M., Tuettenberg A., Knop J. and A.H. Enk. 2001. Identification and
functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated
from peripheral blood. J Exp Med. 4;193(11):1285-94. (IF 13,21)
PhD/MD students (last 5 years)
Michael Maas, Ph.D., 2010
Volker Storn, Ph.D, 2008
.
Sonja Schallenberg, Ph.D.,2008
Kurt Schönfeld, Ph.D., 2008
Yingjie Qian, PhD., 2005
Helmholtz Alliance (HA-202), Melanoma Therapy Targeting, Förderperiode bis 31.12.12
SFB 938 Milieuspezifische Kontrolle immunologischer Reaktivität, 1. Förderperiode bis 31.12.2014
APPENDIX II
82
DR. MED. MORITZ FELCHT
Resident of Dermatology
Department of Dermatology, Venereology, and Allergy,
University Medical Center Mannheim, Heidelberg University
Theodor-Kutzer-Ufer 1-3
68135 Mannheim
0621 383 2280 (Fon)
0621 383 3815 (Fax)
[email protected]
Curriculum Vitae
2008 – to date
2007
Education
2002-2006
2000-2002
02-04/2006
12-01/2005/06
02-03/2004
08-09/2001
Board-certified dermatologist
Resident of Dermatology
Department of Dermatology, Venerology, Allergy
(Prof. Goerdt)
Postdoctoral Studies at
Vascular Biology & Tumor Angiogenesis
Medical Faculty Mannheim, Heidelberg University (CBTM) &
German Cancer Research Center, Heidelberg
(Prof. Augustin)
Resident of General Surgery
University of Schleswig-Holstein, Campus Lübeck
(Prof. Bruch)
Julius-Maximilians-University, Würzburg
Freie University Berlin
Strong Memorial Hospital, University of Rochester, USA
Boston University Medical School, USA
St. Vincent’s Hospital, Geelong, University of Melbourne
(General Medicine), Australia
Bristol Royal Infirmary Hospital (Admission Ward), England
Cancer biology: Vascular Tumor Microenvironment: since 06/2013 Group Leader of the
Juniorgroup “Vascular Tumor Microenvironment” at the Department of Dermatology/ Vascular
Biology & Tumor Angiogenesis Medical Faculty Mannheim, Heidelberg University (CBTM); funded
by the DFG; Tumor angiogenesis: 2008-06/2013 Post-Doctoral studies at the Department of
Vascular Biology & Tumor Angiogenesis Medical Faculty Mannheim, Heidelberg University
(CBTM) & German Cancer Research Center, Heidelberg (Prof. Augustin); Cutaneous Tumor
Development: since 2007 Member of the Working Group of Cutaneous Lymphomas, University
Medical Center Mannheim (Prof. Klemke and Prof. Goerdt); Apoptosis and Cell Death: 20022007 The medical thesis (Dr. med.) analysed “death-receptor-mediated MAP-kinase-activation in
keratinocytes” („Todesrezeptor-vermittelte MAP-Kinasen-Aktivierung in Keratinozyten“; Department
of Dermatology, Venerology, Allergy University of Würzburg (Prof. Leverkus)
83
APPENDIX II
Professional Experience
since 12/2012
2007- to date
Felcht, M.*, W. Koenen*, C. Weiss, K. Weina, C. Geraud, and J. Faulhaber. (2013) Delayed
closure of complex defects with serial tightening of loop sutures – clinical outcome in 64
consecutive patients. J Eur Acad Dermatol doi: 10.1111/jdv.12122; 2013 (IF 2.70) *equal
contribution.
Felcht, M., R. Luck, A. Schering, P. Seidel, K. Srivastava, J. Hu, A. Bartol, Y. Kienast, C. Vettel,
Wieland, C. Klein, M. Thomas, A. Uemura, S. Goerdt, and H.G. Augustin. (2012) Angiopoietin-2
differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest. 122:19912005 (IF 12, 81).
Felcht,* M., M. Heck*, C. Weiss, J. C. Becker, E. Dippel, C. S. L. Müller, D. Nashan, M. M.
Sachse, J. P. Nicolay, N. Booken, S. Goerdt, and C.-D. Klemke. 2012 Expression of the T-cell
regulatory marker FOXP3 in primary cutaneous large B-cell lymphoma cells. Brit J Dermatol. 167:
348-59 (IF 3,76). *equal contribution
Felcht M., N. Booken, P. Stroebel, S. Goerdt, and C.D. Klemke. 2011 The value of molecular
diagnostics in primary cutaneous B-cell lymphoma in the context of clinical findings, histology, and
immunohistochemistry. J Am Acad Dermatol 64: 135-43. (IF 4,91)
Thomas M.*, M. Felcht*, K. Kruse, S. Kretschmer, C. Deppermann, A.V. Benest, U. Fiedler, and
H.G. Augustin. 2010 Angiopoietin-2 stimulation of endothelial cells induces alphavbeta3 integrin
internalization and degradation. J Biol Chem 285: 23842-9. *equal contribution (IF 4,65)
PhD/ MD students
Martin Petkov: PhD: “Analyse des Einflusses der Angiopoietin-like Proteine-3 und -4 auf die
Angiopoietin-2 Signalgebung”, since 2014
Malte Kranert: MD: “Analyse des Tumor-assozierten Gefäßnetzes beim kutanen T-Zell Lymphom”,
since 2013
Christine Stumpf: MD: “Analyse des Tumor-assozierten Gefäßnetzes beim kutanen B-Zell
Lymphom”, since 2011 (together with Prof. Klemke)
APPENDIX II
Robert Luck: Bachelor thesis: “Effects of Angptl-3 and Angptl-4 stimulation of brain pericytes”, 0209/2011 (together with Prof. Augustin)
Philipp Seidel: Master thesis: “Tie2 independent functions of angiopoietin-2 during angiogenesis”,
04-10/2010 (together with Prof. Augustin)
“Analyse des Einflusses der Angiopoietin-like Proteine-3 und -4 auf die Angiopoietin-2 Signalgebung”, 2013-2016 DFG Erstantrag FE 1282/1-1
84
PD DR. MED. CYRILL GÉRAUD
Consultant Physician
Department of Dermatology, Venereology, and Allergology,
68135 Mannheim
0621 383 2126 (Fon)
0621 383 3815 (Fax)
[email protected]
Habilitation (Venia legendi) for Dermatology and Venereology (Medical
Faculty Mannheim, Heidelberg University)
05/2013 - to date
Consultant physician (Oberarzt), Department of Dermatology, Venereology,
and Allergology, University Medical Center Mannheim, Heidelberg University
04/2013
Board Certification in Dermatology and Venereology
09/2012- 04/2013
Senior Resident physician (Funktionsoberarzt), Department of Dermatology,
Venereology, and Allergology, University Medical Center Mannheim,
2008 - 2013
Resident physician, Department of Dermatology, Venereology, and
Allergology, University Medical Center Mannheim, Heidelberg University
2009 - to date
Group leader research group “Organ-specific microvessels” with Prof. Dr.
Sergij Goerdt, Department of Dermatology, Venereology, and Allergology,
2009
Doctoral thesis: Institute of Anatomy und Cell Biology, Department of
Neuroanatomy (Prof. M. Frotscher) of the Albert-Ludwigs-University Freiburg,
Germany: “Involvement of the extracellular matrixprotein Reelin during
differentiation of hippocampal neurons in vitro” (magna cum laude)
2001-2007
Medical Degree: Albert-Ludwigs University Medical School in Freiburg im
Breisgau, Germany with extramural electives in San Diego, CA, USA Internal
Medicine) and Tampa, FL, USA (Dermatology)
Endothelial cells, Organ-Specific Endothelial Differentiation and Function, Dermato-Oncology,
Dermatopathology, Metastasis.
Géraud, C.*, K. Schledzewski*, A. Demory, D. Klein, M. Kaus, F. Peyre, C. Sticht, K. Evdokimov, S.
Lu, A. Schmieder, and S. Goerdt. 2010. Liver sinusoidal endothelium: a microenvironmentdependent differentiation program in rat including the novel junctional protein liver endothelial
differentiation-associated protein-1. Hepatology. 52:313-26. (IF 12.00)
Schledzewski, K.*, C. Géraud*, B. Arnold, S. Wang, H.J. Grone, T. Kempf, K.C. Wollert, B.K.
Kzhyshkowska, and S. Goerdt. 2011. Deficiency of liver sinusoidal scavenger receptors stabilin-1
blood factors. J Clin Invest. 121:703-14. (* K.S. and C.G. contributed equally to this work) (IF
12.812)
85
APPENDIX II
Curriculum vitae
02/2014
Géraud, C.*, C. Mogler*, A. Runge, K. Evdokimov, S. Lu, K. Schledzewski, B. Arnold, G.
Hämmerling, P.S. Koch, K. Breuhahn, T. Longerich, A. Marx, C. Weiss, F. Damm, A. Schmieder, P.
Schirmacher, H.G. Augustin, S. Goerdt. 2013. Endothelial transdifferentiation in hepatocellular
carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival.
Liver Int. 33:1428-40. (IF 3.870)
Géraud, C.*, K. Evdokimov*, B.K. Straub, W.K. Peitsch, A. Demory, Y. Dorflinger, K. Schledzewski,
A. Schmieder, P. Schemmer, H.G. Augustin, P. Schirmacher, and S. Goerdt. 2012. Unique cell
type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids. PLoS
One. 7:e34206. (IF 3.730)
Schmieder, A., K. Schledzewski, J. Michel, J.P. Tuckermann, L. Tome, C. Sticht, C. Gkaniatsou,
J.P. Nicolay, A. Demory, J. Faulhaber, J. Kzhyshkowska, C. Géraud, and S. Goerdt. 2010.
Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2-like
tumor-associated macrophages expressing the novel CD20 homolog MS4A8A. Int J Cancer.
(IF 6.198)
PhD
Siladitta Biswas; Functional characterization of the novel junctional protein liver endothelial
differentiation-associated protein (leda)-1, 2011-2014, together with Prof. Dr. S. Goerdt
Francis Peyre, Tumor-induced endothelial differentiation in vitro, 2007 - 2011, cum laude, together
with Prof. Dr. S. Goerdt
Johanna Zierow,; Molecular mechanisms of liver sinusoidal endothelial differentiation in development,
2013-2017, together with Prof. Dr. S. Goerdt
MD
APPENDIX II
Claudia Ansorge, Organ-spezifische Endothelzelldifferenzierung in vitro, 2010 - 2014, together with
Prof. Dr. S. Goerdt
Konstantin Evdokimov, Characterization of a novel liver endothelial differentiation-associated protein1, 2009 – 2013, summa cum laude, together with Prof. Dr. S. Goerdt
Shun Lu, Characterization of tumor endothelium in a murine model of hepatocellular carcinoma and in
hepatic melanoma metastasis, 2009 – 2010, rite, together with Prof. Dr. S. Goerdt
Manuel Winkler, Functional analysis of liver endothelial differentiation associated protein (Leda) -1 in
malignant melanoma, 2010 - 2014, together with Prof. Dr. S. Goerdt
Molekulare und funktionelle Analyse des neuen junktionalen Proteins Leda-1 in Endothelzellen und
beim malignen Melanom, 2011 – 2014, DFG-Erstantrag GE-2339/1-1
Liver-specific vascular differentiation and function, 2013-2017, Project B1, Collaborative Research
Center (DFG Sonderforschungsbereich) / Transregio 23 (together with Prof. Dr. S. Goerdt)
86
DR. PETER GESERICK
Section of Molecular Dermatology,
68135 Mannheim
0621 383 3990
[email protected]
Curriculum vitae
01.2010 - to date
01.2012 - 06.2012
01.2006 - 12.2009
01.2005 - 12.2005
01.2001 - 12.2004
10.1996 - 09.2000
Postdoctoral Studies, Section of Molecular Dermatology,
(Mannheim)
Parental leave
Postdoctoral
Studies,
Otto-von-Guericke-University
(Magdeburg)
Postdoctoral Studies, Max-Planck-Institute for Infection
biology (Berlin)
PhD in biochemistry to Dr. rer. nat, Max-Planck-Institute for
Infection biology and Free University of Berlin (Berlin)
Study of Biochemistry, University of Potsdam
Signal transduction, Cell death, Inflammation, tumorigenesis, SCC, melanoma
Feoktistova M.*, P.Geserick*, B.Kellert, D.Panayotova-Dimitrova, C.Langlais, M.Hupe, K.Cain,
M.MacFarlain, G.Häcker, and M.Leverkus. 2011. cIAPs block Ripoptosome formation, a
RIP1/caspase 8 containing intracellular cell death complex differentially regulated by cFLIP
isoforms. Mol. Cell. 43(3):449-63. (* equal contribution) (IF 15,28)
Geserick, P., M.Hupe, M.Moulin, and M.Leverkus. 2010. RIP-in CD95L-induced cell death: The
control of alternative death receptors pathways by cIAPs. Cell Cycle. 9(14):2689-2691. (IF 5,24)
Geserick, P., M.Hupe, M.Moulin, W.W.Wong, M.Feoktistova, B.Kellert, H.Gollnick, J.Silke, and
M.Leverkus. 2009. Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase
recruitment. J Cell Biol. 187:1037-1054. (IF 10,82)
Geserick, P., C.Drewniok, M.Hupe, T.L.Haas, P.Diessenbacher, M.R.Sprick, M.P.Schon,
F.Henkler, H.Gollnick, H.Walczak, and M.Leverkus. 2008. Suppression of cFLIP is sufficient to
sensitize human melanoma cells to TRAIL or CD95L-mediated apoptosis. Oncogene. 27:32113220. (IF 7,36)
87
APPENDIX II
Feoktistova M.*, P.Geserick*, D.Panayotova-Dimitrova, and M.Leverkus. 2012. Pick your poison:
the Ripoptosome, a cell death platform regulating apoptosis and necrosis. Cell Cycle. 11(3):460-7.
(* equal contribution) (IF 5,24)
PhD (last 5 years) and titles of their theses
PhD
Jing Wang, Role of BRAF and MEK kinases for death receptor induced cell death in melanoma. (in
progress)
Ramon Schilling, Identification and characterization of novel molecules involved necroptotic signalling
patways in keratinocytes and malignant skin cancer cells, 2012-2015 (in progress)
Sebastian Horn, Identification and characterization of caspase 10 isoforms for cell death signalling
patways in keratinocytes and skin malignancies, 2011-2014 (in progress)
Mike Hupe, The role of DISC-associated signals for apoptotic and non-apoptotic
signalling in keratinocytes, 2006 - 2009, summa cum laude
Maria Feoktistova, The contribution of RIP1 for TRAIL- and TLR3-mediated death signalling in
human keratinocytes, 2005 -2010, magna cum laude
Shyam Kavuri, cFLIP and its splice variants and their role for death receptor-mediated NF-κB and
JNK activation in the skin, 2005 - 2009, cum laude
APPENDIX II
88
PROF. DR. MED. SERGIJ GOERDT
Chairman, Dept. of Dermatology, Venereology, and Allergy,
68135 Mannheim
0621 383 2280 (Fon)
0621 383 3815 (Fax)
[email protected]
Curriculum vitae
since 2013
since 2009
2007-2012
2006-2010
2005-2009
2002-2009
seit 2000
1997-1999
1997
1995-2000
1989-1991
1987/89, 1991/94
1985-1987
1978-1985
Vice Dean, Medical Faculty Mannheim, Heidelberg University
Member of the Board of Collaborative Research Center TRR 23
Speaker of the Excellence Center Dermatology Mannheim of the State of
Baden-Württemberg
Vice Dean for Structure and Development, Med. Faculty Mannheim
Vice Speaker Collaborative Research Center TRR 23 “Vascular
Differentiation and Remodelling”
Member of the Board of Collaborative Research Center SFB 405
“Immuntoleranz und ihre Störungen”
Chairman, Dept. Dermatology, University Medical Center Mannheim,
President, Dermatological Society of Berlin
Associate Professor for Dermatology and Venereology, FU Berlin
Vice Chairman, Dept. Dermatology, UKBF, FU Berlin
Visiting Research Fellow, Harvard Medical School, Boston, MA
Resident, Dept. Dermatology, University of Münster
Research Assistent, Inst. f. Exp. Dermatology, University of Münster
Medical College, Universities of Münster, Mainz, Wien, and Freiburg
Schledzewski, K.*, C. Géraud*, B. Arnold, S. Wang, H.J. Grone, T. Kempf, K.C. Wollert, B.K.
Kzhyshkowska, and S. Goerdt. 2011. Deficiency of liver sinusoidal scavenger receptors stabilin-1
blood factors. J Clin Invest. 121:703-14. (IF 12.81)
Géraud, C.*, K. Schledzewski*, A. Demory, D. Klein, M. Kaus, F. Peyre, C. Sticht, K. Evdokimov,
S. Lu, A. Schmieder, and S. Goerdt. 2010. Liver sinusoidal endothelium: a microenvironmentdependent differentiation program in rat including the novel junctional protein liver endothelial
differentiation-associated protein-1. Hepatology. 52:313-26. (IF 12.00)
Klein, D., A. Demory, F. Peyre, J. Kroll, H.G. Augustin, W. Helfrich, J. Kzhyshkowska, K.
Schledzewski, B. Arnold, and S. Goerdt. 2008. Wnt2 acts as a cell type-specific, autocrine growth
factor in rat hepatic sinusoidal endothelial cells cross-stimulating the VEGF pathway. Hepatology.
47:1018-31. (IF 12.00)
Booken, N., A. Gratchev, J. Utikal, C. Weiss, X. Yu, M. Qadoumi, M. Schmuth, N. Sepp, D.
Nashan, K. Rass, T. Tüting, C. Assaf, E. Dippel, R. Stadler, CD Klemke, and S. Goerdt. 2008.
Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene
signature including diagnostic marker molecules CDO1 and DNM3. Leukemia. 22: 393-399. (IF
10.16)
89
APPENDIX II
Dermato-Oncology, Vascular Biology, Immunology / Innate Immunity
Kzhyshkowska, J., S. Mamidi, A. Gratchev, E. Kremmer, C. Schmuttermaier, L. Krusell, G. Haus, J.
Utikal, K. Schledzewski, J. Scholtze, S. Goerdt. 2006. Novel stabilin-1 interacting chitinase-like
protein (SI-CLP) is upregulated in alternatively activated macrophages and secreted via the lysosomal
pathway. Blood. 107:3221-28. (IF 9.06)
PhD
Biswas, Siladitta; Functional characterization of the novel junctional protein liver endothelial
differentiation-associated protein (leda)-1, 2011-2014, together with PD Dr. C. Géraud
Dollt, Claudia; Identification and characterization of progression-associated TAM molecules in
malignant melanoma, 2013-2017, together with Dr. A. Schmieder
Michel, Julia; Characterization of a novel melanoma-associated TAM molecule, 2010-2014, magna
cum laude, together with Dr. A. Schmieder
Nurgazieva, Dinara; TGFbeta signaling in alternatively activated macrophages, 2008 – 2011, magna
cum laude, together with Prof. Dr. J. Kzhyshkowska
Peyre, Francis; Tumor-induced endothelial differentiation in vitro, 2007 – 2011, cum laude, together
with PD Dr. C. Géraud
Popova, Anna; New mechanism of signal transduction in alternatively activated macrophages, 2006 –
2009, magna cum laude, together with Prof. Dr. J. Kzhyshkowska
Riabov, Vladimir; Analysis of the role of stabilin-1 in tumour growth and its functions in tumourassociated macrophages, 2008–2011, magna cum laude, together with Prof. Dr. J. Kzhyshkowska
Schönhaar, Kathrin; Molecular, phenotypic and functional characterization of the hyaluronan receptor
Lyve-1 as a novel TAM molecule in malignant melanoma, 2011-2014, together with Dr. A. Schmieder
APPENDIX II
Zierow, Johanna; Molecular mechanisms of liver sinusoidal endothelial differentiation in development,
2013-2017, together with PD Dr. C. Géraud
Zhang, JingJing: Mechanism of stabilin-1 mediated endocytosis and ligand trafficking, 2006 – 2011,
summa cum laude, together with Prof. Dr. J. Kzhyshkowska
MD
Claudia Ansorge, Organ-spezifische Endothelzelldifferenzierung in vitro, 2010 - 2014, together with
PD Dr. C. Géraud
Konstantin Evdokimov, Characterization of a novel liver endothelial differentiation-associated protein1, 2009 – 2013, summa cum laude, together with PD Dr. C. Géraud
Gkaniatsou, Cleopatra; Ms4a8a overexpression inhibits tumor growth of CT26 colon carcinoma cells
in vivo, 2009 – 2010, cum laude, together with Dr. A. Schmieder
Kneifel, Simone Alexandra; Standardisierte Versorgung von Weichteildefekten am Schädel, 2007 –
2010, cum laude, together with PD Dr. W. Koenen
90
Linder, Anna Spophie Maria; Retrospektive Analyse von Patienten mit malignen epithelialen
Hauttumoren nach Anwendung von plastischen Rekonstruktionsverfahren, 2007 – 2009, magna cum
laude, together with PD Dr. W. Koenen
Shun Lu, Characterization of tumor endothelium in a murine model of hepatocellular carcinoma and in
hepatic melanoma metastasis, 2009 – 2010, rite, together with PD Dr. C. Géraud
Manousaridis, Ioannis; Gene expression profiling of alternatively activated human blood monocytes
with emphasis on the expression of Wnt-related molecules and FOXQ1. An ex vivo application on
acute atopic dermatitis, 2007 – 2009, magna cum laude, together with PD Dr. A. Gratchev
Teerling, Gloria-Viktoria; Versorgung schichtübergreifender Weichteildefekte am Schädel mit
azellulärem Dermisersatz, 2008 – 2011, cum laude, together with PD Dr. W. Koenen
Wen, Ming; Cloning and characterization of inhibitor of DNA binding 3 (ID3) promoter, 2007 – 2010,
cum laude, together with PD Dr. A. Gratchev
Winkler, Manuel; Functional analysis of liver endothelial differentiation associated protein (Leda) -1 in
malignant melanoma, 2010 - 2014, together with PD Dr. C. Géraud
Tumor-associated macrophages and tumor progression: functional plasticity and progressiondependent TAM target molecules in malignant melanoma, 2011-2014, Project H, Collaborative
Research Center SFB 938
Tumor-specific vascular reprogramming in HCC: mechanisms and therapeutic targets, 2010-2014,
Project C3, Collaborative Research Center TRR77 (together with Prof. Dr. H. Augustin)
APPENDIX II
Liver-specific vascular differentiation and function, 2013-2017, Project B1, Collaborative Research
Center TRR23 (together with PD Dr. C. Géraud)
91
PROF. DR. MED. MARTIN LEVERKUS
Associate Professor for Clinical and Molecular Dermatology
Section of Molecular Dermatology,
68135 Mannheim
0621 383 2344 (Fon)
0621 383 4085 (Fax)
[email protected]
Curriculum vitae
2009 - to date
2006
2004 - 09
2002
2002
2000
2000
1997
1995 - 97
1993 - 94
1993
1985-92
Associate professor (W3) for Clinical and Molecular Dermatology,
Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg
Board approval „Medical Tumor Therapy“
Associate professor (C3) for Clinical and Experimental Dermatology,
Otto-von-Guericke-University Magdeburg
Venia legendi for Dermatology, University of Würzburg
Consultant in Dermatology, Department of Dermatology,
University of Würzburg
Board certification Allergology
Board certification Dermatology
Resident in Dermatology, Department of Dermatology, University of
Würzburg; Establishment of the independent research group
“Apoptosis regulation in the skin”
Postdoctoral Studies, Dermatology Department
of Boston University, Boston, MA, USA
„Arzt im Praktikum“ and Resident in Dermatology, Department of
Dermatology, University of Würzburg
Promotion to Dr. med. (Physiological Institute of the University of Cologne)
MD studies in Cologne, Clermont-Ferrand (France), Johannesburg (South
Africa) and Greenville (USA).
APPENDIX II
Dermato-Oncology, Signal tranduction, Cell death, Inflammation
Feoktistova, M., P.Geserick, B.Kellert, D.P.Dimitrova, C.Langlais, M.Hupe, K.Cain, M.Macfarlane,
G.Hacker, and M.Leverkus. 2011. cIAPs block Ripoptosome formation, a RIP1/caspase-8
containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol. Cell
43:449-463. (IF 15,28)
Geserick, P., C.Drewniok, M.Hupe, T.L.Haas, P.Diessenbacher, M.R.Sprick, M.P.Schon,
F.Henkler, H.Gollnick, H.Walczak, and M.Leverkus. 2008. Suppression of cFLIP is sufficient to
Geserick, P., M.Hupe, M.Moulin, W.W.Wong, M.Feoktistova, B.Kellert, H.Gollnick, J.Silke, and
M.Leverkus. 2009. Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase
recruitment. J Cell Biol 187:1037-1054. (IF 10,82)
Leverkus, M., M.Neumann, T.Mengling, C.T.Rauch, E.B.Bröcker, P.H.Krammer, and H.Walczak.
2000a. Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary
and transformed human keratinocytes. Cancer Res. 60:553-559. (IF 8,65)
92
Leverkus, M., H.Walczak, A.McLellan, H.W.Fries, G.Terbeck, E.B.Brocker, and E.Kämpgen.
2000b. Maturation of dendritic cells leads to up-regulation of cellular FLICE- inhibitory protein and
concomitant down-regulation of death ligand- mediated apoptosis. Blood 96:2628-2631. (IF 9,06)
PhD
Mike Hupe, The role of DISC-associated signals for apoptotic and non-apoptotic
signalling in keratinocytes, 2006 - 2009, summa cum laude
Maria Feoktistova, The contribution of RIP1 for TRAIL- and TLR3-mediated death signalling in
human keratinocytes, 2005 -2010, magna cum laude
Shyam Kavuri, cFLIP and its splice variants and their role for death receptor-mediated NF-κB and
JNK activation in the skin, 2005 - 2009, cum laude
Beate Kellert, Die Rolle des Inflammasoms bei Differenzierung, Reifung und Funktion von
Dendritischen Zellen, 2007 - 2011
MD
Michael Czisch, Die Rolle von Bcl-2 bei der UV- und TRAIL-induzierten Apoptose, 2000 - 2002,
magna cum laude
Moritz Felcht, Die Todesrezeptor-vermittelte MAPK-Aktivierung in humanen Keratinozyten, 2002 2004, magna cum laude
Dominikus Hausmann, Der Einfluss von cFLIP bei der apoptotischen und nichtapoptotischen
Signalgebung durch TRAIL-Rezeptoren in Keratinozyten, magna cum laude
Die Bedeutung von A20 und ABIN-1 für die TNF-vermittelte apoptotische und inflammatorische
Signalgebung von Keratinozyten, 2011 – 2014, DFG Projekt Le 953/6-1.
Generierung und Analyse konditional induzierbarer transgener Tiere zur Funktionsanalyse von
cFLIP in der Haut, 2013 – 2016, DFG Projekt Le 953/8-1.
Resistenz gegenüber Tumor-spezifischen chimären T-Zellen: synergistische Apoptose-Induktion
durch gezielte Hemmung anti-apoptotischer Proteine, 2012 – 2015 (Dt. Krebshilfe, Projekt 109891;
gemeinsam mit Prof. Marx, Institut für Pathologie)
93
APPENDIX II
Barbara Kehler, Zur Bedeutung des TRAIL-R1 bei der Pathogenese und Tumorprogression des
malignen Melanoms, 2007 - 2010
DR. MED. ANKE S. LONSDORF
Attending Physician and Junior Group Leader
University Medical Center Heidelberg,
Ruprecht-Karls-University of Heidelberg
Voßstrasse 2
69115 Heidelberg
06221 56 8505 (Fon)
06221 56 8083 (Fax)
[email protected]
Curriculum vitae
10/2011-date
12/2011- 12/2013
12/2011
02/2011
2008 – 02/11
02/06 – 09/10
2006 – 2008
2006
2004 – 2006
2000 – 2001
04/98-06/04
APPENDIX II
1997-2004
Attending Physician, Dept..of Dermatology, Ruprecht-Karls-University of
Heidelberg and National Centre for Tumor Diseases Heidelberg (NCT),
Germany
Olympia Morata Scholarship of Ruprecht-Karls-University of Heidelberg
Board Certification Medical Tumor Therapy
Board Certification Dermatology and Venerology
Residency, Dept. of Dermatology, Ruprecht-Karls-University of Heidelberg,
Germany
NIH/DFG Research Career Transition Award of the National Institutes of
Health (NIH) and the German Research Foundation (DFG)
Postdoctoral research fellowship, National Institutes of Health (NIH), National
Cancer Institute (NCI), Department of Dermatology, Bethesda, MD, USA
Promotion to Dr. med. (Dept. of Internal Medicine, University of Ulm,
Germany), Thesis: “Intratumor CpG-oligodeoxynucleotide injection induces
protective antitumor T cell immunity”
Residency, Dept. of Dermatology, Ruprecht-Karls-University of Heidelberg,
Germany
Doctoral research fellowship, Case Western Reserve University (CWRU),
Dept. of Pathology, Cleveland, OH, USA
Scholarship of the German National Academic Foundation (Studienstiftung
des deutschen Volkes)
Medical School, Ruprecht-Karls-University of Heidelberg, Germany
Dermato-Oncology, Chemokine Biology, Inflammation, Immunology
Lonsdorf AS, Kraemer BF, Fahrleitner M, Schoenberger T, Gnerlich S, Ring S, Gehring S,
Schneider SW, Kruhlak MJ, Meuth SG, Nieswandt B, Gawaz M, Enk AH, Langer HF: Engagement
of αIIbβ3 (GPIIb/IIIa) with ανβ3 mediates interaction of melanoma cells with platelets - a
connection to hematogeneous metastasis. J Biol Chem. 2012 Jan 13;287(3):2168-78. (IF 4,65)
Chien A.J.*, Moore E.C.*, Lonsdorf A.S., Kulikauskas R.M., Rothberg B.G., Berger A.J., Major
M.B., Hwang S.T., Rimm D.L. and R.T. Moon. 2009. Activated Wnt/beta-catenin signaling in
melanoma is associated with decreased proliferation in patient tumors and a murine melanoma
model. Proc Natl Acad Sci U S A. 27;106(4):1193-8. (IF 9.74) *equal contribution, alphabetical
order
Hedrick, M.N.*, Lonsdorf A.S. *, Shirakawa A.K., Lee Richard C.C, Liao F., Singh S.P., Zhang
H.H., Grinberg A., Love P.E., Hwang S.T. and JM Farber. 2009. CCR6 is required for IL-23-
94
induced psoriasis-like inflammation in mice. J Clin Invest 119:2317-2329. (IF 12,81) * equal
contribution, alphabetical order
Huang, V., Lonsdorf A.S., L. Fang, T. Kakinuma, V.C. Lee, E. Cha, H. Zhang, K. Nagao, M.
Zaleska, W.L. Olszewski, and S.T. Hwang. 2008. Cutting edge: rapid accumulation of epidermal
CCL27 in skin-draining lymph nodes following topical application of a contact sensitizer recruits
CCR10-expressing T cells. J Immunol 180:6462-6466. (IF 5,52)
Lonsdorf, A.S., H. Kuekrek, Stern B.V., Boehm B.O,. Lehmann P.V and M. Tary Lehmann. 2003.
Intratumor CpG-oligodeoxynucleotide injection induces protective antitumor T cell immunity. J
Immunol 171:3941-3946. (IF 5,52)
PhD
Victor Huang, Rapid accumulation of epidermal CCL27 in skin-draining lymph nodes following
topical application of a contact sensitizer recruits CCR10-expressing T cells, 2007-2008
(Institution: National Institutes of Health, Bethesda, USA)
APPENDIX II
MD
Ellen Memaj, Untersuchung der Auswirkungen von UVB, UVA und UVA-1-Bestrahlung auf die
Chemokinexpression humaner Keratinozyten, to date
95
PROF. DR. MED. KNUT SCHÄKEL
Vice Chairmen
Associate Professor for Immunodermatology
Heidelberg University Hospital
Ruprecht-Karls-University, Heidelberg
Voßstr. 2
69115 Heidelberg
06221 56 8447 (Fon)
06221 56 8449 (Fax)
[email protected]
Curriculum vitae
2009 - to date
2009
2008
2005
2004
2003
2000
1995 - 2000
1993 - 1995
1993
1990 - 1991
Vice chairman, Department of Dermatology and Associate Professor (W3),
Ruprecht-Karls-University Heidelberg
Associate Professor (W2), Department of Dermatology, TU Dresden
Consultant Immunologist, German Society of Immunology
Habilitation in Immunology and Venia legendi in Dermatology
Consultant, Department of Dermatology, TU Dresden
Board certificate in Dermatology and Allergy
Resident, Department of Dermatology, TU Dresden
Postdoctoral Research Fellowship, Institute of Immunology, TU Dresden
Resident, Department of Dermatology, Georg-August University of Göttingen
Dissertation, Department of Pediatrics, Medical School Hannover
Predoctoral Research Fellowship, DAAD, State University of New York,
Buffalo, USA
Immunology, Dendritic cells, Innate immunity
APPENDIX II
Döbel, T., A. Kunze, J. Babatz, K. Tränkner, A. Ludwig, M. Schmitz, A. Enk and K. Schäkel. 2013.
FcγRIII (CD16) equips immature 6-sulfo LacNAc-expressing dendritic cells (slanDCs) with a unique
capacity to handle IgG-complexed antigens. Blood. 18:3609-18. (IF 9,89)
Hansel, A., C.Gunther, J.Ingwersen, J.Starke, M.Schmitz, M.Bachmann, M.Meurer, E.P.Rieber,
and K.Schäkel. 2011. Human slan (6-sulfo LacNAc) dendritic cells are inflammatory dermal
dendritic cells in psoriasis and drive strong TH17/TH1 T-cell responses. J. Allergy Clin. Immunol.
127:787-794. (IF 11,0)
Randolph, G.J., G.Sanchez-Schmitz, R.M.Liebman, and K.Schäkel. 2002. The CD16(+)
(FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a
model tissue setting. J. Exp. Med. 196:517-527. (IF 13,38)
Schäkel, K., R.Kannagi, B.Kniep, Y.Goto, C.Mitsuoka, J.Zwirner, A.Soruri, K.M.von, and E.Rieber.
2002. 6-Sulfo LacNAc, a novel carbohydrate modification of PSGL-1, defines an inflammatory type
of human dendritic cells. Immunity. 17:289-301. (IF 21,63)
Schäkel, K., K.M.von, A.Hansel, A.Ebling, L.Schulze, M.Haase, C.Semmler, M.Sarfati,
A.N.Barclay, G.J.Randolph, M.Meurer, and E.P.Rieber. 2006. Human 6-sulfo LacNAc-expressing
dendritic cells are principal producers of early interleukin-12 and are controlled by erythrocytes.
Immunity. 24:767-777. (IF 21,63)
96
PhD
Annette Ebling, Die funktionelle Modifikation der proinflammatorischen M-DC8+ dendritischen
Zellen durch zyklisches Adenosin-Monophosphat. magna cum laude
Anja Hänsel, Programmierung von Th17-1 T-Zellen durch slan-dendritische Zellen und deren
Bedeutung bei Autoimmunerkrankungen. magna cum laude
Thomas Döbel, Immunregulatorische Bedeutung der Expression des Fc-gamma Rezeptors III bei
humanen dendritischen Zellen.
Stephanie Oehrl, Untersuchungen zur Funktion von Inflammasomen bei nativen humanen
dendritischen Zellen
MD
Susanne Baumeister, Einfluss von G-CSF auf die Mobilisation und immunregulatorische Funktion
von slan( 6-sulfo LacNAc+) – dendritischen Zellen, summa cum laude
Matthias von Kietzell, Ausreifung und funktionelle Charakterisierung einer neuen Population von
humanen dendritischen Zellen (slanDC), summa cum laude
Jens Ingwersen, Funktioneller Vergleich von Subpopulationen dendritischer Zellen des
menschlichen Blutes. summa cum laude
Katja Rückert, Einfluss von TACE-Inhibitoren auf die Ausreifung
proinflammatorischer M-DC8+ dendritischer Zellen. magna cum laude
und
Funktion
Adele Heinrich: Einfluss des Anaphylatoxins C5a auf die Funktion proinflammatorischer 6-Sulfo
LacNAc-exprimierender dendritischer Zellen (slanDCs) des humanen Blutes. magna cum laude
Anke Döhring: Untersuchungen anhand eines neuen monoklonalen Antikörpers mit Spezifität für
Fc gamma Rezeptor III (CD16+) exprimierende dendritische Zellen des menschlichen Blutes.
magna cum laude
Untersuchungen zur Bedeutung von pro-inflammatorischen slan-dendritischen Zellen bei der
Psoriasis, 2011 – 2015, Sonderforschungsbereich 938, Projekt N
97
APPENDIX II
Sabine Seibel: Thema: Generierung 6-Sulfo LacNAc-exprimierender dendritischer Zellen
(slanDCs) aus hämatopoetischen Vorläuferzellen. magna cum laude
DR. MED. UNIV. ASTRID SCHMIEDER
Specialist in Dermatology, Venereology, and Allergy
68135 Mannheim
0621 383 2280 (Fon)
0621 383 4085 (Fax)
[email protected]
Curriculum vitae
since 2013
2013
2013
grant
2011
2011
2007 – 2013
2007
2007
2007
2005
2001
1999 – 2007
1999
Senior physician, University hospital Mannheim, Department of Dermatology
Board certification Allergology
Board certification Dermatology2012
Olympia
Morata
Gerok grant of the SFB 938: Milieuspezifische Kontrolle immunologischer
Reaktivität
Poster Award: Synergistic activation by p38MAPK and glucocorticoid
signaling mediates induction of M2-like tumor-associated macrophages
expressing the novel CD20 homolog MS4A8A
Resident, University hospital Mannheim, Department of Dermatology
Italian medical board exam
Promotion to Dr. med. (Institute of pathophysiology at the Universitiy of
Innsbruck, Austria) with the dissertation entiteled: Isogentisin- A novel
compound for the prevention of smoking-caused endothelial injury
Dr. Maria Schaumayer grant
Otto Seibert merit grant
Otto Seibert merit grant
MD Studies in Innsbruck, University of Innsbruck, Austria
Dante Alleghieri award
APPENDIX II
Tumor associated macrophages, Signal transduction, Dermatohistopathology, Psoriasis vulgaris
Michel J, Schonhaar K, Schledzewski K, Gkaniatsou C, Sticht C, Kellert B, Lasitschka F, Geraud
C, Goerdt S, and Schmieder A. 2013. Identification of the novel differentiation marker ms4a8b and
its murine homolog ms4a8a in colonic epithelial cells lost during neoplastic transformation in
human colon. Cell Death Dis 4:e469 (IF 6.04)
Schmieder A, Michel J, Schonhaar K, Goerdt S, and Schledzewski K. Differentiation and gene
expression profile of tumor-associated macrophages. Semin Cancer Biol 22:289-297. (IF 7,44)
Schmieder A*, Schledzewski K*, Michel J, Schonhaar K, Morias Y, Bosschaerts T, Van den
Bossche J, Dorny P, Sauer A, Sticht C, Geraud C, Waibler Z, Beschin A, and Goerdt S. 2012. The
cd20 homolog ms4a8a integrates pro- and anti-inflammatory signals in novel m2-like macrophages
and is expressed in parasite infection. Eur J Immunol 42:2971-2982. (IF 4.97)
Schmieder A*, Schledzewski K*, Michel J, Tuckermann JP, Tome L, Sticht C, Gkaniatsou C,
Nicolay JP, Demory A, Faulhaber J, Kzhyshkowska J, Geraud C, and Goerdt S. 2011. Synergistic
98
activation by p38mapk and glucocorticoid signaling mediates induction of m2-like tumor-associated
macrophages expressing the novel cd20 homolog ms4a8a. Int J Cancer 129:122-132. (IF 6.20)
Schmieder A*, Schwaiger S*, Csordas A, Backovic A, Messner B, Wick G, Stuppner H, Bernhard
D. 2007. Isogentisin--a novel compound for the prevention of smoking-caused endothelial injury.
Atherosclerosis. 194:317-325. (IF 3,71)
Michel, Julia; A comprehensive functional analysis of the CD20 homolog MS4A8A in macrophages
and colonocytes (2010-2014).
Schönhaar, Kathrin; Identification and characterization of progression-associated TAM molecules
in malignant melanoma (2011-2014).
Claudia, Dollt; Identification of signalling pathways essential for the development of TAM
phenotypes in malignant melanoma (2013-2016).
MD students (last 5 years) and titles of their theses
Cleopatra, Gkaniatsou; Ms4a8a over-expression inhibits tumr growth of CT26 colon carcinoma
cells in vivo (2009-2010). Cum laude
Daniel, Behr; Charakterisation of the inflammatory infiltrate in the merkel cell carcinoma (20132014).
APPENDIX II
SFB 938 (2011-2014), Projekt H, S. Goerdt: Tumor-assoziierte Makrophagen (TAM) und
Tumorprogression: funktionelle Plastizität und progressionsabhängige TAM-Targetmoleküle beim
Malignen Melanom
99
PROF. DR. MED. STEFAN WERNER SCHNEIDER
Associate Professor for Clinical and Experimental Dermatology
Section of Experimental Dermatology,
68135 Mannheim
0621 383 6902 (Fon)
0621 383 6903 (Fax)
[email protected]
Curriculum vitae
Since 12/08
12/08
09/08
10/07
APPENDIX II
06/07
06/06
04/06
since 2005
04/05
08/02
03/02
07/01
since 11/00
03/99
11/97
10/97-06/02
08/97-09/97
08/96-09/97
08/94-07/96
05/95
07/94
05/94
11/89-02/94
11/87-05/94
Head of the Section “Experimental Dermatology” and Assistant Medical
Director (“Leitender Oberarzt”) at the Department of Dermatology,
Venereology and Allergology
W3 “Cellular Differentation” University Mannheim-Heidelberg due the
nomination of the Department of Dermatology Mannheim (Director: Prof. Dr.
Sergij Goerdt) as the “Exzellenzzentrum Dermatologie in BadenWürttemberg”.
specialized in phlebology
Award for „innovative medical technology“ received from Federal Ministry of
Education and Research (BMBF) by Ms Dr. A. Schavan
Apl-Professur
Senior supervisor at the Department of Dermatology, University of Münster
Specialized in dermatology, allergy and venerology
Development aid in Cambodia (regularly in Phnom Penh)
Oskar-Gans-Award (Dermatology)
Specialized in physiology
Department of Dermatology, University of Münster (Prof. Dr. T. Luger)
Habilitation (Venia legendi in Physiolgy)
Head of working group „cell dynamics“
Bennigsen-Foerder-Award
Approbation
Department of Physiology, University Münster (Prof. Dr. H. Oberleithner)
Fellowship (Anniversary award University Würzburg) at Department of
Cellular and Molecular Physiology, Yale University, USA
Dept. Internal Medicine University Hospital Würzburg (Prof. Dr. K. Wilms)
DFG-Fellowship at Dept. of Physiology Univ. Würzburg (Prof. Dr. H.
Oberleithner), Dept. of Surgery and Cellular Physiology, Yale University,
USA (Prof. Dr. J. Geibel/Prof. Dr. G. Giebisch)
Franconian Science Prize in Human Medicine
Received Dr. of Medicine („Summa cum Laude“)
Medical License at University of Würzburg
Doctoral Thesis (Prof. Dr. H. Oberleithner, Physiology, Univ. of Würzburg)
School of Medicine University Würzburg, Izmir (Turkey), Chur (CH)
Mechanism of melanoma cell invasion and adhesion, Endothelial cell biology, von Willebrand
factor, endothelium - tumor cell communication, mechanism of metastasis, new innovative medical
technologies (5D-Intravitaltomography, micro-/nanofluidic, RICM, atomic force microscopy).
100
Görge, T., A.Barg, E.M.Schnäker, B.Pöppelmann, V.Shpacovitch, A.Rattenholl,
T.A.Luger, M.Steinhoff, and S.W.Schneider. 2006. Melanoma-derived MMP-1 targets endothelial
PAR1 promoting endothelial cell activation. Cancer Res. 66:7766-74. (IF 8,65)
Pappelbaum, K.I., C.Gorzelanny, S.Grässle, J.Suckau M.W.Laschke, M.Bischoff, C.Bauer,
M.Schorpp-Kistner, C.Weidenmaier, R.Schneppenheim, T.Obser, B.Sinha, and S.W.Schneider.
2013. Ultra-large von Willebrand factor fibers mediate luminal Staphylococcus aureus adhesion to
an intact endothelial cell layer under shear stress. Circulation 128:50-59. (IF 15,20)
Riehemann, K, S.W.Schneider, T.A.Luger, B.Godin, M.Ferrari, and H.Fuchs. 2009. Nanomedicine: challenge and oppurtunities. Angewandte Chemie, Int. edition 48:872-97, 2009. (wurde
auch in deutscher Sprache publiziert) (IF 13,455)
Kerk, N., E.A.Strozyk, B.Pöppelmann, and S.W.Schneider. 2010. The mechanism of melanomaassociated thrombin activity and von Willebrand factor release from endothelial cells. J Invest
Dermatol. 130(9):2259-68. (IF 6,314)
Schneider, S. W., S.Nuschele, A.Wixforth, A.Alexander-Katz, R.R.Netz, C.Gorzelanny, and
M.F.Schneider. 2007. Shear-induced unfolding triggers adhesion of vWf fibers. Proc Natl Acad Sci
USA 104:7899-903. (IF 9,74)
PhD
Dr. rer. nat. Chrisitan Gorzelanny, Bioaktivität von Chitosan an Endothel-, Leukozyten und
Tumorzellen, 2005-2008, Auszeichnung der Universität Münster
Dipl.-biol. Anna Desch, Melanom-Endothel Kommunikation: Mechanismen der Endothelzellaktivierung und Bedeutung für die Metastasierung, 2009-andauernd
MD
Dr. med. Andre Niemeyer, Folgen der extrazelulärer Azidose an humanen Endothelzellen, 20002006
Dr. med. Afschim Fatemi, Effektive Therapie der Hyperhidrosis mittels Suctionscürettage, 20062007
Dr. med. Alexej Barg, Polymersierung des von-Willebrand Faktors in vitro, 2002-2007,
Promotionspreis der Universität Münster
Zahnärztin Katharina Podolewski, Die Bedeutung der ProteinaseActivated-Rezeptors (PAR) für die
Melanomzellinvasion, 2004-2008
Arzt Felix Kleinrüschkamp, Mechanismen der Extravasation von Melanomzellen, Bedeutung des
endothelialen von-Willebrand Faktors als Adhäsionsmolekül, 2005-2011
Dr. med. Nina Kerk, Melanom-Endothel Kommunikation: Aktivierung des endothelialen
Weges und dessen Folge für die Expression von Adhäsionsmolekülen, 2007-2011
101
nFkB
APPENDIX II
Dipl.-biol. Karin Pappelbaum, Staphylokokken-Endothel Adhäsion und Endothelzellaktivierung:
Bedeutung der Chitotriosidase, 2009-andauernd
cand. med. Karin Roters, Wirkung von Pimecrolimus auf die Keratinozytenfunktion und –
morphologie, 2007-andauernd
cand. med. Margit Esser, Rasterkraftmikroskopische Untersuchungen nativer Alters- und Steroidgeschädigter Haut, 2007-andauernd
cand. med. Verena Niemeyer,
Flußbedingungen, 2009-andauernd
Melanomzelladhäsion
am
Endothel
unter
definierten
cand. med. Jan Suckau, ULVWF in Tumorgefäßen der Maus und Mensch, 2010-andauernd
cand. Med. Sarah Schober; Rutin und Vitamin C als effective Therapie der Purpura Pigmentosa
Progressiva, 2011-andauernd
cand. med. Lukas Görtz, Melanom-Endothelzell Kommunikation im lymphatischen System, 2011andauernd
SFB/TR 23 (TP A9) Vascular differentiation and remodelling “Mechanism controlling the transition
from quiescent to activated endothelium cells mediated by tumor cells”, 07.2013-06.2017
BMBF „Anwendung der Intravitaltomographie (Woundoptomizer) an chronischen Wunden”,
10.2010-12.2013
DFG Wissenschaftliche Forscherguppe „Shear flow regulated hemostasis“, (SCHN 474/5-1);
10.2011 bis 09.2014
EU Verbundprojekt „Nano3Bio (Nr. 616931)“, 10.2013-09.2017
APPENDIX II
102
PROF. DR. JONATHAN P. SLEEMAN
Franz-Volhard-Stiftungsprofessur für Mikrovaskuläre
Biologie und Pathobiologie (W3)
Ludolf-Krehl-Str 13-17
68167 Mannheim
0621 383 9955 (Fon)
0621 383 9961 (Fax)
[email protected]
Curriculum vitae
2008–to date: W3-Franz-Volhard-Stiftungsprofessur
für
Mikrovaskuläre
Biologie
und
Pathobiologie, Universität Heidelberg (Medizinische Fakultät Mannheim)
2008–to date: Group leader, Karlruhe Institute of Technology, Institut für Toxikologie und Genetik
(secondary employment basis)
2004 - 2007: Acting Chair of Genetics (W3), Institut für Genetik, University of Karlsruhe
2002 – 2007 Deputy Director, Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik
2000
Habilitation (Fach: Genetik), University of Karlsruhe
1997 - 2007: Group leader, Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik
1992-1996: Postdoctoral studies, Forschungszentrum Karlsruhe, Institut für Genetik
EMBO long-term fellowship (1992-1993)
Marie Curie Fellow of the European Union (1994-1996)
1987-1991: PhD degree, Trinity College, Cambridge University, England
1984-1987: 1st Class Honours Degree in Natural Sciences, specialising in Biochememistry.
Trinity College, Cambridge University, England
1983-1984: „Break Year Student“, Department of Cancer Studies, University of
Birmingham, England
Sleeman, J.P., Rudy, W., Hofmann, M., Moll, J., Ponta, P. and Herrlich, P. 1996. Regulated
clustering of variant CD44 proteins increases their hyaluronate binding capacity. J. Cell Biol., 135:
1139-1150. (IF 10.82)
Thiele, W., Krishnan, J., Rothley, M., Weih, D., Plaumann, D., Kuch, V., Quagliata, L., Weich, H.,
Pytowski, B. and Sleeman, J. P. 2012. VEGFR-3 is expressed on megakaryocyte precursors in
the murine bone marrow and plays a regulatory role in megakaryopoiesis. Blood, 120: 1899-1907.
(IF 9.06)
Nestl, A., Von Stein, O., Zatloukal, K., Thies, W.-G., Herrlich, P., Hofmann, M and Sleeman, J. P.
2001. Gene expression patterns associated with the metastatic phenotype in rodent and human
tumors. Cancer Research, 61: 1569-1577. (IF 8.65)
Krishnan, J., Kirkin, V., Steffen, A., Hegen, M., Weih, D., Tomarev, S., Wilting, J. and Sleeman, J.
P. 2003. Differential in vivo and in vitro expression of VEGF-C and VEGF-D in tumors and its
relationship to lymphatic metatasis in immunocompetent rats. Cancer Research, 63: 713-722 (IF
8.65)
Baumann, P., Cremers, N., Kroese, F., Orend, G., Chiquet-Ehrismann, R., Uede, T., Yagita, H. and
Sleeman, J. P. 2005. CD24 expression causes the acquisition of multiple cellular properties
associated with tumor growth and metastasis. Cancer Research, 65: 10783-10793 (IF 8.65)
103
APPENDIX II
Metastasis, lymphangiogenesis
2010 Nicole Grau. Zur Rolle von Lymphknotenmetastasen in der Metastasierung von Tumoren in
lebenswichtige Organe.
Note: 1,0 (sehr gut)
2011 Anja Schmaus. Regulation der Lymphangiogenese: Moleküle, Mechanismen und die Rolle
in pathologischen Prozessen.
Note: 1,0 (sehr gut), Summa cum lauda
2011 Luca Quagliata. Local, regional and systemic roles of VEGF-C in tumor metastasis.
Note: Magna cum lauda
2012 Jochen Bauer. Die Rolle niedermolekularer Hyaluronsäurefragmente und LYVE-1 bei der
Lymphangiogenese.
2012 Vanessa Kuch. Evaluierung und Identifizierung zuverlässiger Methoden zur Isolierung von
Krebsstammzellen.
Note: Summa cum lauda
2013 Anna Poletti. Protein interaction partners of ASAP1 and their role in metastasis.
Current PhD students: Haniyeh Sabouri, Justyna Krachulec, Sandra Klusmeier, Supriya Saraswati,
Lisa Jerabek
HGF Biointerfaces Joint/Twinning Programme. Cell-free metabolic cascades for the enzymatic
synthesis of tailor-made oligosaccharides using microfluidic devices (together with PD Dr. Ute Schepers and
Prof. Dr. Matthias Franzreb)
Baden-Württemberg Stiftung Forschungsprogramm „Glykobiologie / Glykomik“ Consortium:
„Glykobiologie von Hyaluronsäure-Oligosacchariden:
biologische und klinische Relevanz“. Coordinator: Jonathan Sleeman
EU Interreg Consortium „Nanomatrix“ Nanoparticles for imaging the lymphatics. Coordinator:
Genevieve Pourroy (France)
APPENDIX II
DAAD PhD Stipendium
Wilhelm Sander-Stiftung The functional interplay between CD24, Src, miR-21, Pdcd4 and u-PAR,
and its impact on invasion and metastasis (together with Prof. Dr. Heike Allgayer).
German-Israeli Foundation (GIF) The role of VEGF-C in the mobilization of immune cells
following anti-cancer drug therapy, and their impact on tumor re-growth and metastasis (together
with Yuval Shaked)
104
PROF. DR. VIKTOR UMANSKY
Group leader, Clinical Cooperation Unit Dermato-Oncology,
German Cancer Research Center (DKFZ) and
Department of Dermatology,
Venereology, and Allergy, University Medical Center Mannheim,
68135 Mannheim
0621 383 3373 (Fon)
0621 383 2163 (Fax)
[email protected]
1972-1978
Study of medicine at the State Medical Institute, Kiev, Ukraine
1982
Ph.D. degree in “Experimental Oncology and Immunology”, Institute for Oncology,
Kiev
1991
Doctor of Science degree in “Experimental Oncology and Immunology”, Institute for
Oncology, Kiev
2001
Habilitation (Venia Legendi) in “Pharmacological Biology” and the acquisition of the
Title “Privatdozent”, Faculty for Phramacology, University Heidelberg, Heidelberg,
Germany
2008
Acquisition of the Title “Professor”, Faculty for Biosciences, University Heidelberg
1979-1982
PhD Student. Department of Molecular Immunology, Institute of Biochemistry, Kiev,
Ukraine
1983-1986
Research associate. Department of Tumor Metastasis, Institute for Oncology, Kiev
1986-1988
Senior research associate. Department of Tumor Metastasis, Institute for Oncology,
Kiev
1988-1991
Leader of the group “Immune Antitumor Resistance”. Department of Tumor
Metastasis, Institute for Oncology, Kiev.
1991-1992
Postdoc. Laboratory of Immunology, INSERM U.252, Dijon, France.
1992-1994
Postdoc. Department of Cellular Immunology, Tumor Immunology Program,
German Cancer Research Center (DKFZ), Heidelberg, Germany
1994-1996
Research associate. Department of Cellular Immunology, DKFZ.
1996-1998
Senior research associate. Department of Cellular Immunology, DKFZ.
1998-2001
Leader of the group “Tumor Immunotherapy”
Department of Cellular Immunology, DKFZ
2001-2002
Leader of the laboratory of Immunology.
Company Virofem Diagnostica, Wiesbaden, Germany
2002-present Leader of the group “Mouse Models of Spontaneous Melanoma for Immunotherapy”.
Skin Cancer Unit, DKFZ and University Hospital Mannheim, Germany
2002
Sir Hans Krebs Prize 2001 for the outstanding work in the biomedical science
entitled “Therapy of human tumors in NOD/SCID mice with patient derived
reactivated memory T cells from bone marrow“ and published in Nature Medicine
2001, 7: 452-458
105
APPENDIX II
Curriculum vitae
Tumor immunotherapy, immunosuppression,
suppressor cells, effector and regulatory T cells
cancer
and
inflammation,
myeloid-derived
5 selected (most important) publications (Impact Factor 2012)
Meyer, C., A. Sevko, M. Ramacher, A.V. Bazhin, C.S. Falk, W. Osen, I. Borrello, M. Kato, D.
Schadendorf, M. Baniyash, V. Umansky. 2011. Chronic inflammation promotes myeloid derived
suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model.
Proc. Natl. Acad. Sci. USA, 108: 17111-17116. (IF = 9.74)
Umansky, V., O. Abschuetz, W. Osen, M. Ramacher, F. Zhao, M. Kato, D. Schadendorf. 2008.
Melanoma specific memory T cells are functionally active in ret transgenic mice without
macroscopical tumors. Cancer Res. 68: 9451-9458. (IF = 8.65).
Beckhove, P., M. Feuerer, M. Dolenc, F. Schuetz, C. Choi, N. Sommerfeldt, J. Schwendemann, K.
Ehlert, P. Altevogt, G. Bastert, V. Schirrmacher, V. Umansky. 2004. Specifically activated memory
T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors. J.
Clin. Invest. 114: 67-76. (IF = 12.81)
Feuerer, M., P. Beckhove, N. Garbi, Y. Mahnke, A. Limmer, M. Hommel, G. Hämmerling, B.
Kyewski, A. Hamann, V. Umansky, V. Schirrmacher. 2003. Bone marrow as a priming site for Tcell responses to blood-borne antigen. Nature Med. 9: 1151-1157. (IF = 22.86)
Feuerer, M., P. Beckhove, L. Bai, E.F. Solomayer, G. Bastert, I.J. Diehl, C. Pedain, M.
Oberniedermayr, V. Schirrmacher, V. Umansky. 2001. Therapy of human tumors in NOD/SCID
mice with patient derived re-activated memory T cells from bone marrow. Nature Med. 7: 452-458.
(IF = 22.86)
PhD
APPENDIX II
Abschütz, Oliver. Melanoma antigen specific memory T cells in transgenic mouse model of
spontaneous melanoma, cum laude, 2005-2008.
Zhao, Fang. Tolerogenic dendritic cells in ret transgenic mouse model of spontaneous melanoma,
magna cum laude, 2006-2009.
Kimpfler, Silvia. Characterization of CD4+CD25+FOXP3+ regulatory T cells in ret transgenic
mouse melanoma model and in melanoma patients, magna cum laude, 2006-2010.
Meyer, Christiane. Effect of myeloid-derived suppressor cells on the expression of T cell receptor
ζ-chain and on melanoma development in ret transgenic mouse model, magna cum laude, 20062010.
Flores-Guzman, Fernando. Dormant tumor cells in ret transgenic mouse melanoma model and
their interaction with T cells, magna cum laude, 2008-2012.
Stemke, Anastasia. Immunotherapy with tumor antigen-specific T cells in ret transgenic mouse
melanoma model, cum laude, 2009-2013.
Ivan Shevchenko. Extracellular adenosine metabolism in melanoma and pancreatic cancer, magna
cum laude, 2010-2013.
106
In situ ablation of primary tumors to induce anti-tumor T-cell reactions and neutralize
immunosuppresive tumor microenvironment. 2012-2014. German-Israeli Foundation for Scientific
Research and Development (GIF).
The role of CCR5 in the recruitment of myeloid-derived suppressor cells (MDSC) from the bone
marrow to support melanoma progression. 2013-2016. DKFZ/MOST Cooperation Program in
Cancer Research.
APPENDIX II
Combined immunotherapy of malignant melanoma using dendritic cell vaccination and
neutralization of immunosuppression in pre-clinical mouse models. 2014-2017. German-Israeli
Helmholtz Research School in Cancer Biology (DKFZ-WIS).
107
PROF. DR. MED. JOCHEN UTIKAL
Head of the Clinical Cooperation Unit Dermato-Oncology,
German Cancer Research Heidelberg (DKFZ) and
Department of Dermatology, Venereology and Allergology,
University Medical Center Mannheim, University of Heidelberg
68135 Mannheim
+49-(0)621-383-4461 (Fon)
+49-(0)621-383-3815 (Fax)
[email protected]
Curriculum vitae
since 3/2012
2009-2012
12/2009
2007-2009
2007
2007
2006
2002-2006
2001
2001
1994-2001
Head of the Clinical Cooperation Unit Dermato-Oncology , German Cancer
Research Center (DKFZ) and Dept. of Dermatology, Venereology and
Allergology, University Medical Center Mannheim, Ruprecht-Karl University
of Heidelberg
Attending (Oberarzt) and Research Group Leader, Department of
Dermatology, Venereology and Allergology, University Medical Center
Mannheim, Ruprecht-Karl University of Heidelberg
Venia legendi for Dermatology and Venereology, Ruprecht-Karl University of
Heidelberg
Research Fellowship Massachusetts General Hospital, Cancer Center and
Harvard Stem Cell Institute, Boston
Medical board certification “Medical Tumor Therapy“
Medical board certification “Allergology”
Medical board certification “Dermatology and Venereology”
Resident in Dermatology, Department of Dermatology, Venereology and
Allergology, University Medical Center Mannheim, Ruprecht-Karl University
of Heidelberg
Resident, Dept. of Dermatology, University of Ulm
Doctoral thesis: The significance of the c-myc and bcl-2 gene in the
pathogenesis of malignant melanoma “summa cum laude”
Study of Medicine at the Universities of Ulm and Berne
APPENDIX II
Translational Dermato-Oncology, Malignant Melanoma, Stem Cells
Honors and Awards (since 2008):
2011 Fleur-Hiege Memorial Award
2010 Hella Bühler-Award for Cancer Research of the Ruprecht-Karl University of Heidelberg
2010 Egon Macher Award
Hirata A*, Utikal J*, Yamashita S, Aoki H, Watanabe A, Yamamoto T, Okano H, Bardeesy N,
Kunisada T, Ushijima T, Hara A, Jaenisch R, Hochedlinger K, Yamada Y. 2013. Dose-dependent
roles for canonical Wnt signalling in de novo crypt formation and cell cycle properties of the colonic
epithelium. Development. 140: 66-75. *authors contributed equally (IF 6,20)
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC,
Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton
MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D.
2012. Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. N Engl J Med. 367:10714. (IF 51,65)
108
Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, Khalil A, Rheinwald JG,
Hochedlinger K. 2009. Immortalization eliminates a roadblock during the reprogramming of somatic
cells into iPS cells. Nature 460:1145-8. (IF 38,59)
Utikal J, Maherali N, Kulalert W, Hochedlinger K. 2009. Sox2 is dispensable for the
reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell Sci
122:3502-10. (IF 5,87)
Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. 2008. Induced pluripotent stem cells
generated without viral integration. Science 322:945-9. (IF 31,02)
PhD
Bernhardt, Mathias; Reprogramming of melanoma cells into a pluripotent state. 2011-2014
Galach, Marta; Dissection of molecular mechanisms of keratinocyte differentiation from iPS cells.
2010-2014
Korona, Danuta; Generation of tumor-antigen-specific T cells from induced pluripotent stem cells (iPS
cells) for melanoma immunotherapy. 2013-2016; together with Viktor Umansky
Schöler, Nathalie; Melanoma stem cell markers and epigenetic plasticity. 2012-2015
Weina, Kasia; Differentiation mechanisms of iPS cells into melanocytes. 2012-2015
MD
Lichtenberger, Ramtin; Biomarker of malignant melanoma, 2012-2014
German research council (DFG, SFB 873, A-8, PI 2010-2014 and SFB636, B-07, PI 2012-2015)
Hella Bühler-Award 2010
Baden-Württemberg Foundation (Adult stem cells II, PI) 2010- 2015
German Cancer Aid, Max-Eder Research Group 2011-2015
BMBF, DZHK 2012-2015
109
APPENDIX II
Orouji, Elias; Diagnostic markers of malignant melanoma, 2011-2014
PROF. DR. MED. FRANK WINKLER
Consultant
Dpt.of Neurooncology
Neurology Clinic and National Center for Tumor Diseases
69120 Heidelberg
06221 56 37772 (phone)
06221 56 5935 (fax)
[email protected]
Curriculum vitae
since 4/2012
W3 Professorship “Experimental Neurooncology”, University of Heidelberg
since 2010
Consultant and Assistant Professor, Dpt. of Neurooncology, University of Heidelberg
Establishment and PI of the research group “Experimental Neurooncology”
2010
Venia Legendi for Neurology, University of Munich (2011: University of
Heidelberg)
2009
Boards in Neurology
2005-2010
Resident, Dpt. of Neurology, University of Munich, Großhadern clinic.
Establishment and PI of the research group “Experimental Neurooncology”.
2003 and 2004
Research Fellow, Steele Lab, Harvard University, Boston (Rakesh Jain)
1999-2002
Resident and Postdoctoral studies, Dpt. of Neurology, University of Munich,
Großhadern clinic
1998
Doctoral thesis (degree Dr. med., Dpt. of Cardiology, Univ. Freiburg), and
Approbation
1994 – 1998
MD studies, University of Freiburg
1991-1994
MD studies, University of Hamburg
2002
2010
Scientific award of the Paul-Ehrlich-Gesellschaft
Sibylle-Assmus Award for Neurooncology
APPENDIX II
Neuro-oncology; brain metastasis of melanoma and lung carcinoma; in vivo imaging, angiogenesis,
invasion
von Baumgarten L, Brucker D, Tirniceru A, Kienast Y, Grau S, Burgold S, Herms J, Winkler F
(2011). Bevacizumab has differential and dose-dependent effects on glioma blood vessels and
tumor cells. Clin Cancer Res 17:6192-205. (IF 7.8)
Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert W, Goldbrunner R, Herms J, F Winkler. 2010.
Real-time imaging reveals the single steps of brain metastasis formation. Nature Med 16: 116-122.
(IF 24.3)
Winkler F, Kienast Y, Fuhrmann M, von Baumgarten L, Burgold S, Mitteregger G, J Herms. 2009.
Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral
angiogenesis. Glia 57:1306-15. (IF 5.1)
Winkler F, Kozin SV, Tong RT, Chae S, Booth MF, Garkavtsev I, Xu L, Hicklin DK, Fukumura D, di
Tomaso E, Munn LL, RK Jain RK. 2004. Kinetics of vascular normalization by VEGFR2 blockade
governs brain tumor response to radiation: Role of oxygenation, Angiopoietin-1, and matrix
metalloproteinases. Cancer Cell 6: 553-563. (IF 24.8)
110
Garkavtsev I, Kozin SV, Chernova O, Xu L, Winkler F, Brown E, Barnett GH, RK Jain. 2004. The
candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis.
Nature 428: 328-32. (IF 38.6)
PhD/MD students (last 5 years)
Yvonne Kienast, PhD: “The mechanisms of brain metastasis formation: a new experimental
approach via in vivo two-photon microscopy”. 2005-2009. Summa cum laude.
Gergely Solecki, PhD student: “Optimization of vascular normalization by anti-VEGF-A and antiAng-2 therapy for improved chemotherapy and radiotherapy”. Started 11/2012.
Mustafa Syed, MD student: “Calcium communication between glioma cells in vitro and in vivo”.
Started 1/2013.
Erik Jung, MD student: “Inhibiting intercellular communication in brain tumors for improved
antitumor therapies”. Started 2/2014
Kianush Karimian, MD student: “Advanced fluorescent reporter systems for dynamic detection of
intratumoral heterogeneity in brain tumor progression”. Started 11/2013
Die Bedeutung der Tumor-Stammzellen für die einzelnen Schritte der Gehirnmetastasierung.
2011-2014. Deutsche Forschungsgemeinschaft, Projekt WI 1930/5-1
Die Wirkung der HER2-Expression, und anti-HER2/-VEGF Therapien auf die einzelnen Schritte
der Hirnmetastasierung von Brustkrebszellen. 2009-2012. Deutsche Krebshilfe, Projekt 109051.
APPENDIX II
Glioma Angiogenesis collaboration. 2012-2014. Roche, Deutschland, Euro 300.000
111
Appendix II
2. Biographical Sketches of the Associated Researchers
PROF. DR. MED. CLAUS-DETLEV KLEMKE
Consultant, Dept. of Dermatology, Venereology, and Allergy,
68135 Mannheim
0621 383 2280 (Fon)
0621 383 3815 (Fax)
[email protected]
APPENDIX II
Curriculum vitae
1989
„Abitur“ (high school degree)
1989-1991
Compulsory Military Service
1991-1998
Medical studies at the Universities of Würzburg, London and Berlin
1998
„Ärztliche Prüfung“ (National Medical Examination); „Approbation“ (Medical board
certification as a physician)
1999-2000
Resident, Dept. of Dermatology, Free University of Berlin
2000
Doctoral Certification, University of Würzburg, „magna cum laude“
2000-2003
Resident, Dept. of Dermatology, Venereology, and Allergology, University Medical
Center Mannheim, University of Heidelberg
2003
„Facharzt für Haut- und Geschlechts-krankheiten“ (Medical board certification for
dermatology and venereology)
2004-2006
Postdoc in the Division of Immunogenetics, Tumour Immunology Program, German
Cancer, Research Center (DKFZ), Heidelberg, Germany
2006
„Zusatzbezeichnung für Allergologie“ (Medical board certification for allergic
diseases)
2007
„Zusatzbezeichnung Medikamentöse Tumortherapie“ (Medical board certification for
medical tumor therapy (chemotherapy))
Since 2007 Speaker of the German working group on cutaneous lymphomas of the ADF
(Arbeitsgemeinschaft Dermatologische Forschung)
2010
Habilitation Dermatologie und Venerologie
2011
„Zusatzbezeichnung Dermatohistologie“ (Medical board certification for
dermatopathology)
2013
Ernennung zum außerplanmässigen Professor der Universität Heidelberg
Dermato-Oncology, Immunology, Apoptosis
Kießling MK, Oberholzer PA, Mondal C, Karpova MB, Zipser MC, Lin WM, Girardi M, MacConaill LE,
Kehoe SM, Hatton C, French LE, Garraway LA, Polier G, Klemke CD, Krammer PH, Gülow K,
Dummer R. High-throughput mutation profiling and next-generation sequencing of CTCL samples
reveal KRAS and NRAS mutations which sensitize tumors towards treatment with inhibitors targeting
the RAS/RAF/MEK signaling cascade. Blood. 2011;117:2433-2440. (IF 10.56)
Steininger A, Möbs M, Ullmann R, Köchert K, Kreher S, Anagnostopoulos I, Hummel M, Richter J,
Beyer M, Janz M, Klemke CD, Stein H, Dörken B, Sterry W, Schrock E, Mathas S, Assaf C. Genomic
loss of the putative tumor suppressor gene E2A promotes lymphoma in human. J Exp Med.
2011;208:1585-93. (IF 14.78)
112
Klemke CD*, Brenner D*, Weiss EM, Schmidt M, Leverkus M, Gülow K, Krammer PH. The lack of T
cell receptor induced signaling is crucial for CD95 ligand up-regulation and protects cutaneous T cell
lymphoma cells from Activation-Induced Cell Death. Cancer Res. 2009;69:4175-4183, *”equal
contribution author” (IF 8.23)
Heid JB, Schmidt A, Oberle N, Goerdt S, Krammer PH, Suri-Payer E*, Klemke CD*. FOXP3+CD25tumor cells with regulatory function in Sézary Syndrome. J Invest Dermatol. 2009;129:2875-85,
*”equal contribution author” (IF 6.27)
Klemke CD*, Fritzsching B*, Franz B, Kleinmann E, Oberle N, Poenitz N, Sykora J, Banham AH,
Roncador G, Goerdt S, Krammer PH, Suri-Payer E. Paucity of FOXP3+ cells in skin and peripheral
blood distinguishes Sézary Syndrome from other cutaneous T cell lymphomas. Leukemia
2006;20:1123-9., *”equal contribution author” (IF 8.97)
MD
Julia Heid, Charakterisierung regulatorischer T Zellen beim Kutanen T Zell Lymphom, 2006 - 2008,
summa cum laude, together with Prof. Dr. P. H. Kramer
Melanie Faust; Analyse der Bedeutung regulatorischer T-Zellen bei kutanen Arzneimittelreaktionen,
2006 – 2013
Joana Schmidt; Auswertung zur klinischen Relevanz von allergologischen Testungen bei
Unverträglichkeitsreaktionen auf Arzneimittel, 2011 – 2013
Jasmin Hambsch, Analyse der Behandlungsparameter bei der Extrakorporalen Photopherese, 2011 –
2013
Daniela Gräf, Retrospektive Auswertung zur Strahlentherapie kutaner Lymphome, 2012-2013.
113
APPENDIX II
Christine Stumpf; Analyse der Expression von Angiopoietin-2 relevanter Proteine in primär kutanen BZell Lymphomen, 2011 – 2013, together with Dr. M. Felcht
PROF. DR. MED. WIEBKE KATHARINA LUDWIG-PEITSCH
Consultant (“Oberärztin”)
Dept. of Dermatology, Venereology and Allergy,
68135 Mannheim
Germany
Phone: +49-621-383 1054
Fax. +49-621-383 3815
Email: [email protected]
Curriculum vitae
Since 06/2012
07/2012
Since 07/2011
Since 10/2010
Since 09/2009
07/2008
02/2008
02/2006-08/2008
07/2005
04/2003
03/2002-01/2006
APPENDIX II
03-12/2002
09/2000-02/2002
05/2000
10/1993-05/2000
06/1993
Grants
04/2004-05/2007
04-12/1999
03/1994-07/2000
Awards
10/2007
06/2007
06/2001
06/1998
Professor of Dermatology and Venereology, Medical Faculty Mannheim,
Specialist in Medical Tumor Therapy
Head of the Division of Allergy, Occupational and Environmental Medicine,
Department of Dermatology, University Medical Center Mannheim,
Deputy Head of the Outpatient Clinic, Department of Dermatology, University
Medical Center Mannheim
Consultant ("Oberärztin"), Department of Dermatology, University Medical
Center Mannheim
Postdoctoral Lecture Qualification ("Habilitation") in Dermatology and
Venereology, Medical Faculty Mannheim, Heidelberg University
Specialist in Allergy
Senior Physician ("Funktionsoberärztin"), Department of Dermatology,
University Medical Center Mannheim
Specialist in Dermatology and Venereology (“Fachärztin”)
Dissertation in Medicine, University of Hamburg in cooperation with the
Division of Cell Biology, German Cancer Research Center, Heidelberg
(grade: summa cum laude)
Senior Resident ("Assistenzärztin"), Department of Dermatology, University
Medical Center Mannheim
Research Appointment, Division of Cell Biology (Head: Prof. Dr. rer. nat.
Werner W. Franke), German Cancer Research Center, Heidelberg
Junior Resident ("Ärztin im Praktikum"), Department of Dermatology and
Venereology, University Hospital Eppendorf, Hamburg, Germany
Medical State Exam (grade: 1.5)
Medical studies, Heidelberg University, Germany; Harvard Medical School,
Boston, MA, USA; University of Texas, Texas, USA
A-levels, Goetheschule, Essen, Germany (grade: 1.0)
Olympia-Morata Scholarship, Heidelberg University
Grant by the German Academic Exchange Service (DAAD)
Grant by the German National Merit Foundation (“Studienstiftung des
deutschen Volkes”)
Award for Experimental Research in Oncology, Working Group for Oncology
(“Onkologischer Arbeitskreis“, OAK), Medical Faculty Mannheim, Heidelberg
University
Karl-Freudenberg-Award of the Heidelberg Academy of Sciences
Award for publications by junior scientists from Northern German
Dermatologic Hospitals, Lübeck, Germany
Student Award, Benjamin Franklin Contest, Berlin, Germany
114
Dermato-Oncology (Malignant Melanoma, Merkel Cell Carcinoma), Cell Adhesion, Actin-binding
Proteins, Psoriasis
Schrama D, Peitsch WK, Zapatka M, Kneitz H, Houben R, Eib S, Haferkamp S, Moore PS, Shuda
M, Thompson JF, Trefzer U, Pföhler C, Scolyer RA, Becker JC. 2011. Merkel cell polyomavirus
status is not associated with clinical course of merkel cell carcinoma. J Invest Dermatol 131:16318. (IF: 6.19)
Schmitt CJ, Franke WW, Goerdt S, Falkowska-Hansen B, Rickelt S, Peitsch WK. 2007. Homoand heterotypic cell contacts in malignant melanoma cells and desmoglein 2 as a novel solitary
surface glycoprotein. J Invest Dermatol 127:2191-2206. (IF: 6.19)
Peitsch WK, Hofmann I, Bulkescher J, Hergt M, Spring H, Bleyl U, Goerdt S, Franke WW. 2005.
Drebrin, an actin-binding, cell-type characteristic protein: induction and localization in epithelial skin
tumors and cultured keratinocytes. J Invest Dermatol 125:761-74. (IF: 6.19)
Peitsch WK, Hofmann I, Endlich N, Prätzel S, Kuhn C, Spring H, Gröne HJ, Kriz W, Franke WW.
2003. Cell biological and biochemical characterization of drebrin complexes in mesangial cells and
podocytes of renal glomeruli. J Am Soc Nephrol 14:1452-63. (IF: 8.98)
Kontoyiannis DK, Peitsch WK, Reddy BT, Whimbey EE, Han XY, Bodey G., Rolston KV.
Cryptococcosis in patients with cancer. Clin Infect Dis 2001; 32:E145-150. (IF: 9.37)
MD students and titles of their theses
Schmitt, Christian; Homo- and heterotypic melanoma cell contacts and desmoglein 2 as a novel
solitary cell surface protein, 2005-2008, summa cum laude, together with Prof. Dr. S. Goerdt.
Werling, Anna Maria; Homo- and heterotypic cell contacts of Merkel cells and Merkel cell carcinomas:
surprising heterogeneity and indications for a cadherin switch, 2008-2010, magna cum laude.
Warnecke, Christine; Cardiovascular and metabolic comorbidities in psoriasis: a case-control study,
2009-2012, magna cum laude.
Schaarschmidt, Marthe-Lisa; Conjoint analysis: a novel method for identification of patient preferences
for psoriasis treatments, 2009-2012, magna cum laude, together with Dr. A. Schmieder.
Vlahova, Lyubomira; P-cadherin: a novel prognostic marker in Merkel cell carcinomas, since 2010,
under review.
Schober, Sarah; Antioxidants as novel treatment approach in pigmented purpuric dermatosis: a
retrospective case series, since 2010, together with Prof. Dr. S. W. Schneider.
Poppe, Manuel; Impact of fumaric acid esters on cardiovascular and metabolic risk factors in
psoriasis, since 2011, together with Dr. A. Schmieder.
Martin, Isabelle; Patient preferences for treatment of basal cell carcinomas: a conjoint analysis, since
2012, together with Dr. A. Schmieder.
Glocker, Anne; Surgical and conservative treatment of basal cell carcinomas: correlation of patient
preferences with subjective and objective success, since 2012, together with Dr. A. Schmieder.
115
APPENDIX II
Lang, Sabine; Inpatient and outpatient treatment of psoriasis – a health economic cost analysis from
the societal perspective, 2006-2009, cum laude, together with Prof. Dr. M. Goebeler.
Kromer, Christian; Patient preferences for treatment of psoriasis with biologicals, since 2012, together
with Dr. M.-L. Schaarschmidt and Dr. A. Schmieder.
Extramural funding
Desmoglein 2 in malignant melanomas: cellular functions, diagnostic and prognostic significance,
2008-2011, project 108626, German Cancer Aid (“Deutsche Krebshilfe”).
Topogenic and regulatory principles of the actin-binding protein drebin, 2006-2008, project PE
896/1-3, German Research Foundation (“Deutsche Forschungsgemeinschaft“).
Molecular characteristics, complexes and functions of the actin-binding protein drebrin in nonneuronal cells, 2003-2006, projects PE 896/1-1 and 1-2, German Research Foundation.
APPENDIX II
116
PROF. DR. RER. NAT. KARSTEN MAHNKE
University Hospital Heidelberg
Ruprecht Karls University Heidelberg
Voßstraße 2
69115 Heidelberg
Phone: +49 6221 56 8170
Fax +49 6221 561617
[email protected]
Curriculum Vitae
2004 - to date
Apl. Prof. Head of Research Laboratory for Dermatology
2003
Venia Legendi in Immunology (Habilitation, PD), University of Mainz, Mentor
Prof. Dr. A. H. Enk
2001 - 2004
Postdoctoral Assistant (C1), Department of Dermatology, University of Mainz,
Prof. A.H. Enk
1996 - 2001
Research Assistant “Laboratory of Cellular Physiology and Immunology”, The
Rockefeller University New York, USA, Prof. R.M. Steinman.
1994 - 1996
Postdoc in the Department of Dermatology, University of Münster, Prof. T.
Schwarz
1990 - 1994
Doctoral thesis in Immunology, Dr. rer. nat, Institute for Dermatological
Research, University of Münster, Prof. C. Sorg
1990
Diploma Thesis in Neurophysiology, University of Münster, Prof E. Speckmann
1983 - 1989
Study of Biology, at the Universities Bremen, Oldenburg, and Münster,
Germany
Ring S, Enk AH, Mahnke K. 2011. Regulatory T cells from IL-10-deficient mice fail to suppress
contact hypersensitivity reactions due to lack of adenosine production. J Invest Dermatol.
131:1494-502. (IF 6,2)
Ring S, Karakhanova S, Johnson T, Enk, A.H. and Mahnke K. 2010. Gap junctions between
regulatory T cells and dendritic cells prevent sensitization of CD8+ T cells. J. Allergy Clin. Immunol.
125:237-247. (IF 10,3)
Ring S, Enk AH, Mahnke K. 2010. Adenosine triphosphate (ATP) activates regulatory T cells
(Treg) in vivo during contact hypersensitivity reactions. J. Immunol. 184:3408-3416. (IF 5,1)
Bedke T, Pretsch L, Karakhanova S, Enk AH, Mahnke K. 2010. Endothelial cells augment the
suppressive function of CD4+ CD25+ Foxp3+ regulatory T cells: involvement of programmed
death-1 and IL-10. J Immunol. 184:5562-70. (IF 5,1)
Ring S, Oliver SJ, Cronstein BN, Enk AH, Mahnke K. 2009. CD4(+)CD25(+) regulatory T cells
suppress contact hypersensitivity reactions through a CD39, adenosine-dependent mechanism. J
Allergy Clin Immunol. 123:1287-96. (IF 10,3)
117
APPENDIX II
Dendritic cells, Regulatory T cells, Allergy, Tumorimmunology
PhD Students
Michael Maas. Targeting dendritischer Zellen mittels DEC205-Rezeptor-spezifischer Single
chain Fragment variable zur Inhibition von Toleranz sowie zur Induktion von Immunität 20082011. Cum laude
Sabrina Schmitt. Funktion und Induktion regulatorischer T-Lymphozyten im murinen Modell der
Multiplen Sklerose und während Graft-versus-Host Erkrankung nach Stammzelltherapie. 20072010. Magna cum laude.
MD Students
Anna Pushkarevskaya. Analysis of CHS reactions in CD73 deficient mice. 2013 ongoing.
Current funding
DFG Einzelantrag. Bis 3/2014 “Intrazelluläres Targeting des Antigenrezeptors DEC-205“.
APPENDIX II
118
PROF. DR. MED. HUGO H. MARTI
C3 Professor for Physiology
University of Heidelberg
Institute of Physiology and Pathophysiology
69120 Heidelberg
06221 54 4138 (Fon)
06221 54 4562 (Fax)
[email protected]
Curriculum vitae
since 20032001-2003
2001
1996-2001
1992-1996
1991-1992
1991
1983-1990
C3 Professor and leader of AG Neurovascular Physiology, Institute of
Physiology and Pathophysiology, University of Heidelberg, Germany
Group leader, Institute of Physiology, University of Zürich, Switzerland
Venia legend for Physiology (University of Giessen)
Research Associate, Max-Planck-Institute for Physiological and Clinical
Research (Prof. W. Risau), Bad Nauheim, Germany
Postdoctoral Associate, Institute of Physiology (Prof. C. Bauer),
University of Zürich
Postgraduate Course in Experimental Medicine and Biology,
University of Zürich
Promotion to Dr. med. (University of Zürich)
Medical College, University of Zürich, Switzerland
Hypoxia and Ischemia, Neurovascular Biology, Blood-Brain Barrier
Schoch HJ, Fischer S, Marti HH. 2002. Hypoxia-induced vascular endothelial growth factor
expression causes vascular leakage in the brain. Brain 125: 2549-2557. (IF 9,92)
Wang Y, Kilic E, Kilic U, Weber B, Bassetti C, Marti HH*, Hermann DM* (*equal contribution).
2005. VEGF overexpression induces post-ischemic neuroprotection, but facilitates hemodynamic
steal phenomena. Brain 128: 52-62. (IF 9,92)
Cvetanovic M, Patel J, Marti HH, Kini AR, Opal P. 2011. VEGF ameliorates the ataxic phenotype
in spinocerebellar ataxia type 1 (SCA) mice. Nature Med 17:1445-7. (IF 22,86)
Kunze R, Zhou W, Veltkamp R, Wielockx B, Breier G, Marti HH. 2012. Neuron-specific prolyl-4hydroxylase domain 2 knockout reduces brain injury after transient cerebral ischemia. Stroke
43:2748-56. (IF 6,16)
119
APPENDIX II
Marti HH, Risau W. 1998. Systemic hypoxia changes the organ-specific distribution of vascular
endothelial growth factor and its receptors. Proc Natl Acad Sci USA 95: 15809-15914. (IF 9,74)
Philipp Barteczek, Einfluss der neurone-spezifischen FIH-1-Defizienz bei zerebraler Ischämie, MD,
2014-2015
Jieming Lin, Einfluss von Fumarsäure-Estern auf das Verhalten von Neuronen unter ischämischen
Bedingungen, MD, 2013-2014
Daniel Gruneberg, Einfluss der neuronen-spezifischen PHD2-Defizienz auf das räumliche Gedächtnis
bei zerebraler Oligämie, MD, 2013-2014,
Li Lexiao, Role of the PHD-FIH-HIF axis for the endogenous adaptive response against ischemic
stroke, PhD, 2013 – 2016,
Reischl Stefan, Effekte der PHD-Inhibition auf die Integrität der Blut-Hirn-Schranke unter
ischämischen Bedingnungen, MD; 2012-2014
Bauer Alexander, Molekulare Mechanismen hypoxie-induzierter Permeabilitätserhöhung an der BlutHirn-Schranke, Dr. sc. hum., 2005-2010, magna cum laude
Springmann Georg, Inhibierung der hypoxiebedingten Permeabilitätserhöhung in zerebralen Gefäßen
durch Blockade des VEGF /VEGF-Rezeptor Systems, MD, 2007-2010, cum laude
Mühlhofer Wolfgang; Transienter neuroprotektiver Effekt von B-Vitaminen bei experimenteller
Epilepsie im Mausmodell, MD, 2007-2010, magna cum laude, together with Prof. J. Schenkel
Staub Janina, Effekte einer permanenten unilateralen Ligatur der arteria carotis communis auf
cognitive Verhaltensparameter sowie Proteinexpression und Apoptose im Gehirn VEGF-transgener
C57Bl/6 Mäuse, MD, 2006- 2010, magna cum laude, together with Prof. K. Plaschke
Die Rolle von PHD2 für die Regeneration nach Schlaganfall, 2013-2015, Else Kröner Fresenius
Stiftung (Kunze/Marti)
APPENDIX II
Protektion vor ischämischem Schlaganfall durch Hemmung der Prolyl-4-Hydroxylasen, 2013-2015,
B. Braun-Stiftung
120
DR. MARTIN RONALD SPRICK
Junior Group Leader at HI-STEM gGmbH
(Heidelberg Institute for Stem Cell Technology
and Experimental Medicine) at the
DKFZ Heidelberg, Germany
Phone:
+49-6221-423913
Fax:
+49-6221-423902
E-mail:
[email protected]
2006-2009
EMBO Postdoctoral Fellow
Laboratory for Experimental Oncology and Radiobiology, AMC UvA, Amsterdam,
The Netherlands. (Head of Group: Prof. Jan Paul Medema)
2004-2006
Postdoctoral Fellow
Group for Apoptosis Regulation, DKFZ Heidelberg, Germany
(Head of Group: Dr. Henning Walczak)
1999-2004
PhD Student and PhD Thesis
„Biochemical analysis of the TRAIL-death inducing signalling complex“. Summa cum
Laude . DKFZ Heidelberg, Germany and University of Konstanz, Germany.
Supervision by Prof. Peter Krammer and Dr. Henning Walczak
1998-1999
Diploma Study and thesis
Differential Signal-Transduction and Gene-Expression in Ha-Ras Transformed LiverEpithelial Cells”. Grade 1.0. University of Konstanz, Germany. Supervision by Prof.
Ernesto Bade
Experimental Oncology, Cancer Stem Cells, Cell Death, Cancer Models
5 selected (most important) publications (Impact Factor 2012)
Hofner T, Macher-Goeppinger S, Klein C, Rigo-Watermeier T, Eisen C, Pahernik S, Hohenfellner
M, Trumpp A, Sprick, M.R. 2013. Development and characteristics of preclinical experimental
models for the research of rare neuroendocrine bladder cancer. J Urol. 190(6):2263-70. (IF 3.67)
Borovski, T., P. Beke, O. van Tellingen, H. M. Rodermond, J. J. Verhoeff, V. Lascano, J. B.
Daalhuisen, J. P. Medema and M. R. Sprick. 2012. Therapy-resistant tumor microvascular
endothelial cells contribute to treatment failure in glioblastoma multiforme. Oncogene.
doi:10.1038/onc.2012.172. (IF 7.38)
Sprick, M. R., M. A. Weigand, E. Rieser, C. T. Rauch, P. Juo, J. Blenis, P. H. Krammer and H.
Walczak. 2000. FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are
essential for apoptosis mediated by TRAIL receptor 2. Immunity 12(6): 599-609. IF (19.80)
Vermeulen, L., E. M. F. De Sousa, M. van der Heijden, K. Cameron, J. H. de Jong, T. Borovski, J.
B. Tuynman, M. Todaro, C. Merz, H. Rodermond, M. R. Sprick, K. Kemper, D. J. Richel, G. Stassi
and J. P. Medema. 2010. Wnt activity defines colon cancer stem cells and is regulated by the
microenvironment. Nat Cell Biol 12(5): 468-476. (IF 20.76)
121
APPENDIX II
Curriculum vitae
2009-present Junior Group Leader at HI-STEM GmbH (Heidelberg Institute for Stem Cell
Technology and Experimental Medicine),
Vermeulen, L., M. Todaro, F. de Sousa Mello, M. R. Sprick, K. Kemper, M. Perez Alea, D. J.
Richel, G. Stassi and J. P. Medema. 2008. "Single-cell cloning of colon cancer stem cells reveals a
multi-lineage differentiation capacity." Proc Natl Acad Sci U S A 105(36): 13427-13432. (IF 9.74)
PhD
Borovski, Tijana; Cancer Stem Cell Niche: The Place to Be.
2007-2012. Co-promoter. Center of Experimental and MolecularMedicine of the Academic Medical
Center (AMC) in Amsterdam, The Netherlands.
2012, Anja Schillert: “Identification and functional analysis of slowly cycling cells in colorectal cancer”
(Co-Supervision with Prof. Trumpp)
2012, Christian Eisen: “Development and investigation of a novel model system representing all three
subtypes of pancreatic ductal adenocarcinoma revelas novel biomarkers and distinct drug
sensitivities” (Co-Supervision with Prof. Trumpp)
2013, Steve Wagner ”Identification of Tumor Initiating Cells in a Patient-Matched Model of Serous
Ovarian Carcinoma” (Co-Supervision with Prof. Trumpp)
APPENDIX II
122
Appendix III
APPENDIX III
Declarations regarding Section 9.2 “Collaboration with other Cooperation Partners”
123
124
125
126
127
128
Deutsche Forschungsgemeinschaft
Herrn Dr. Anselm Fremmer
Kennedyallee 40
D-53175 BONN
Germany
December 18, 2013
Research Training Group „Hallmarks of Skin Cancer“
Dear Dr. Fremmer,
On behalf of King’s Health Partners and the St. John’s Institute of Dermatology, I am
delighted to commit faculty and facilities to support the Research Training Group “Hallmarks
of Skin Cancer”.
We are extremely excited by the potential for innovative developments in this highly
important, but under-studied area. Prof. Goerdt and his colleagues have assembled an
outstanding set of investigators across the Mannheim-Heidelberg faculties and the German
Cancer Research Centre. We commit to supporting their efforts by pairing investigators with
outlined projects creating opportunities for intense scientific collaboration, consultation and
trainee mobility to work in the laboratories of the members of the London faculty. The London
faculty of the RTG provides thorough expertise across a spectrum of relevant basic science
and clinical practise.
We shall also work together to establish a regular scientific exchange with our German
collaborators and the students by co-organizing yearly British-German Workshops on Skin
Cancer Biology that will mutually be held at the St. John’s Institute or at the Institutes of the
Heidelberg-Mannheim Skin Cancer Alliance. As you may be aware, the St John’s Institute
has a world-leading reputation for translational research excellence that goes back many
decades. Thus, it can be immensely valuable for the students in the training programme to
learn how the Institute has achieved its goals in this critically important arena.
We look forward to an excellent interaction that can at the same time promote scientific and
clinical progress in skin cancer as well as the development of a new cadre of researchers in
this key biomedical area.
Sincerely,
Adrian Hayday, PhD, FMedSci.
Kay Glendinning Professor of Immunobiology,
King’s College London School of Medicine.
129
Co-Lead Clinical Academic Grouping in Genetics, Rheumatology, Infection, Immunity &
Dermatology,
King’s Health Partners.
Guy’s Hospital, London SE1 9RT., UK
Senior Group Leader,
London Research Institute,
Cancer Research UK.
London, WC2A 3LY, UK
130

II - Hallmarks of Skin Cancer

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