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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.
Research Area A – Cancer Cell Dissemination
The processes leading to skin cancer dissemination and metastasis are complex and far from being completely understood.
Project Package A1: Cancer Stem Cells
As in other cancers, metastasis in MM and SCC follows an ordered sequence of events. However, the MM- and 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).
P1: The role of Id proteins in determining the tumor initiating and metastatic properties of melanoma cells
(PI J. Sleeman; London PI: C. Hill)
P2: Characterization of human melanoma cells on the basis of markers of pluripotent stem cells
(PI: J. Utikal; London PI: F. Watt)
P3: The role of Wnt signaling in tumor-initiating cells and tumor progression in cutaneous SCC
(PI: I. Augustin, M. Boutros; London PI: F. Watt)
P4: Identification of genes linked to aberrant Wnt signaling in melanoma
(PI: M. Boutros; London PI: B. Baum)
Project Package A2: Invasion and Metastasis
Enhanced motility and invasive capacity are mediated in part by epithelial-mesenchymal transition and 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).
P5: Function of the mucin-like glycoprotein podoplanin in squamous cell carcinoma progression
(PI: P. Angel; London PI: J. Burchell)
P6: Crosstalk between melanoma cells and the blood-brain barrier: impact on coagulation and brain metastasis to identify new anti-metastatic targets
(PI: S. W. Schneider, F. Winkler; London PI: A. Dorling)
P7: Liver-specific endothelial mechanisms of melanoma metastasis
(PI: C. Géraud, S. Goerdt; London PI: I. Malanchi)
Research Area B – Primary Resistance to Cell Death and Immunity
Resistance to cell death occurs in malignant tumors as they develop into high grade malignancies, and accompanies resistance to treatment in general.
Project Package B1: Primary Resistance to Cell Death
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 family 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 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.
P8: Does Angiopoietin-2 protect malignant melanoma tumor cells from anoikis?
(PI: M. Felcht, H. Augustin; London PI: K. Hodivala-Dilke)
P9: The regulation of Ripoptosome-associated cell death pathways in keratinocyte skin cancer
(PI: M. Leverkus; London PI: P. Meier)
P10: IAP antagonists: A novel therapeutic option to overcome cell death resistance in malignant melanoma?
(PI: P. Geserick, M. Leverkus; London PI: H. Walczak)
Project Package B2: Primary Resistance to Tumor Immunity
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).
P11: Characterization and modulation of CC-chemokine receptor 6 (CCR6) mediated immunosurveillance in malignant melanoma
(PI: A. Lonsdorf, A. Enk; London PI: F. Balkwill)
P12: Tumor-directed cytotoxicity of proinflammatory human dendritic cells and natural killer cells in malignant melanoma (MM)
(PI: K. Schäkel, A. Cerwenka; London PI: F. Geissmann)
P13: Regulation of tumor-associated macrophage and myeloid-derived suppressor cell activation and its neutralization in transgenic mouse melanoma model
(PI: A:Schmieder, V. Umansky; London PI: S. Diebold)