Dissection of TRAIL-mediated signaling in pancreatic ductal adenocarcinoma cells - towards efficient anti-tumor therapy

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Based on a superior tumor-specific activity, TRAIL is currently viewed as a promising candidate biological response modifier for anti-cancer therapy. Several clinical studies with TRAIL and agonistic anti-TRAIL receptor antibodies are currently performed, although preclinical data showing potentially pro-tumoral effects have been reported and the detailed dissection of TRAIL-signaling especially regarding the specific roles of each of the two pro-apoptotic TRAIL- receptors (TRAIL-Rl and TRAIL-R2) is still missing. Furthermore, the influence of the tumor stroma on TRAIL-Rl and TRAlL-R2-signaling has not yet been addressed. Using sophisticated techniques to analyse membrane and intracellular receptor complexes as well as coculture experiments and animal models we will further characterize signaling of both TRAIL receptors in pancreatic ductal adenocarcinoma (PDAC) cells and clarify its dependance on tumor stroma as well as on endogenous TRAIL, TNF and CD95L. Our project will allow the development of supportive treatment modalities selectively maximizing the anti-tumor effect and suppressing proliferative and metastatic side-effects of TRAIL anti-cancer therapy.