Project 7

1. Applicant

2. Topic

Sensitization of melanoma cells for death ligand-mediated apoptosis

Abb. 1: Ein typisches Merkmal apoptotischer Zellen ist die Zellkern-Fragmentierung, hier gezeigt für Melanomzellen nach Apoptose-Induktion und Anfärbung des Zellkerns.
Abb. 2: Der Todesligand TRAIL bindet an 4 Rezeptoren (TRAIL-R1, TRAIL-R2, DcR-1 und DcR-2), von denen aber nur die ersten beiden agonistisch sind und über das Adapterprotein FADD eine proapoptotische Caspasen-Kaskade sowie den Transkriptionsfaktor NF-kappaB aktivieren.

3. Short summary

Death ligands as CD95L/FasL and TRAIL secreted by tumor-infiltrating T-lymphocytes critically contribute to induction of apoptosis in target cells. Especially, TRAIL is a promising candidate for tumor therapy due to its selective proapoptotic effects in neoplastic cells. Melanoma cells responded sensitive to death ligands however different resistance mechanisms were identified in the preparatory work in vitro and in mouse models. These were related to death receptor loss (CD95, TRAIL-R1) or inactivation (TRAIL-R2), an altered ratio of anti- to proapoptotic Bcl-2 proteins (Bcl-2/Bax) or downregulation of initiator caspases. Targeting death ligand resistance in melanoma may on one hand support an anti-tumor immune response and may on the other hand facilitate TRAIL-related therapeutic strategies. In this project, melanoma cell models for death ligand resistance will be further developed and in particular, relations to survival pathways as MAPK, PKB/Akt and NF-kB will be investigated. In this way, suitable strategies for overcoming death ligand resistance shall be identified in vitro and shall be checked in mouse models. Relevant markers will also be identified in melanoma biopsies, in a retrospective immunohistological study. The contributory role of death ligands in new melanoma therapies shall be defined and suitable combinations for efficient targeting of melanoma shall be identified.  

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