Role of the calcium channel TRPV6 in the progression of pancreatic ductal adenocarcinoma

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The present project is a joint thesis project (co-tutelle) between the University of Lille, (FR) and the University of Münster (DE). The project description below includes both, the French and the German part. Funding has already been approved by the University of Lille for 18 months so that funding is requested only for the German part which has a duration of 18 months, too.Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death. Its incidence is growing (- estimated 2nd most frequent cause of cancer-related death in 2030 -) at a time when many other cancers are in decline. Although our knowledge on the genetics and epidemiology of PDAC has greatly advanced during the last years, the molecular mechanisms that give rise to PDAC aggressiveness are far from being clear and have not yet delivered targeted therapies. Increasing evidences suggest that the overexpression of a Ca2+ channel, TRPV6, is a common and pathophysiologically relevant phenomenon in cancers of epithelial origin such as those from ovary, prostate, breast, thyroid and colon. Thus, a phase I clinical trial has already been performed with a TRPV6 blocker in patients with such cancers. TRPV6 is also expressed in pancreatic ducts. Moreover, its mutation gives rise to early-onset chronic pancreatitis which in turn is a risk factor for developing PDAC. We therefore hypothesize, that the TRPV6 channel, being recognized as a proto-oncogene in many tumors, plays an important role in PDAC progression. The unique pH landscape in the exocrine pancreas and in PDAC together with the pH sensitivity and Ca2+ permeability of TRPV6 could make this channel an attractive modulator of PDAC cell aggressiveness.In order to test this hypothesis we will adress the follwing specific research aims:1) Define the role of the TRPV6 channels in pancreatic cancer cell proliferation, apoptosis resistance, migration and invasion in vitro and elucidate the underlying signal transduction pathways.2) Clarify in vivo the role of TRPV6 channels in tumor growth and progression.3) Identify a correlation of TRPV6 channel expression with the tumor grade as well as the patients’ outcome in a retrospective study of patient material.As a fundamental part of the project, we will be the first to demonstrate the functional role of the TRPV6 channel in PDAC progression. Our results will further indicate whether TRPV6 channels may serve as a diagnostic and/or prognostic tool in clinical practice.