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

本项目是里尔大学（法国）和明斯特大学（德国）之间的联合论文项目（共同监护）。以下项目说明包括法文和德文部分。里尔大学已经批准了为期18个月的资助，因此只要求德国部分的资助，期限也是18个月。胰腺导管腺癌（PDAC）是癌症相关死亡的第四大常见原因。它的发病率正在增长（估计2030年癌症相关死亡的第二大原因），而此时许多其他癌症正在下降。尽管我们对PDAC的遗传学和流行病学的了解在过去几年中有了很大的进步，但引起PDAC侵袭性的分子机制还远未明确，并且尚未提供靶向治疗。越来越多的证据表明，Ca 2+通道TRPV 6的过表达是上皮来源的癌症如卵巢癌、前列腺癌、乳腺癌、甲状腺癌和结肠癌中常见的病理生理相关现象。因此，已经在患有这种癌症的患者中使用TRPV 6阻断剂进行了I期临床试验。TRPV 6也在胰管中表达。此外，它的突变引起早发性慢性胰腺炎，这反过来又是发展PDAC的风险因素。因此，我们假设TRPV 6通道在许多肿瘤中被认为是原癌基因，在PDAC进展中起重要作用。胰腺外分泌和PDAC中独特的pH景观以及TRPV 6的pH敏感性和Ca 2+渗透性可能使该通道成为PDAC细胞侵袭性的有吸引力的调节剂。 明确TRPV 6通道在体外胰腺癌细胞增殖、凋亡抵抗、迁移和侵袭中的作用，并阐明潜在的信号转导途径。 阐明体内TRPV 6通道在肿瘤生长和进展中的作用。 通过对患者资料的回顾性研究，确定TRPV 6通道表达与肿瘤分级以及患者预后的相关性。作为该项目的基础部分，我们将首次证明TRPV 6通道在PDAC进展中的功能作用。我们的研究结果将进一步表明TRPV 6通道是否可以作为临床实践中的诊断和/或预后工具。

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.