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

钙通道TRPV6在胰腺导管腺癌进展中的作用

• 批准号: 455225310
• 负责人: Professor Dr. Albrecht Schwab
• 金额: --
• 依托单位: Institut für Physiologie II (Vegetative Physiologie)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/455225310?language=en
• 关键词: Role; calcium; channel; TRPV6; progression

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.

本项目是里尔大学(FR)和明斯特大学(DE)的联合论文项目。下面的项目描述包括法国部分和德国部分。里尔大学已经批准了为期18个月的资助，因此只需要为德国部分申请资助，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。在许多其他癌症正在下降的时候，它的发病率却在增长(据估计，2030年癌症相关死亡的第二大常见原因)。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，但导致PDAC侵袭性的分子机制还远远不清楚，也还没有提供有针对性的治疗方法。越来越多的证据表明，在卵巢、前列腺癌、乳腺癌、甲状腺癌和结肠癌等上皮性肿瘤中，钙通道TRPV6的过度表达是一种常见的病理生理相关现象。因此，已经用TRPV6阻滞剂对此类癌症患者进行了I期临床试验。TRPV6在胰管中也有表达。此外，它的突变会导致早发性慢性胰腺炎，这反过来又是发展为PDAC的危险因素。因此，我们假设，在许多肿瘤中被认为是原癌基因的TRPV6通道在PDAC的进展中起着重要的作用。为了验证这一假说，我们将介绍以下具体的研究目标：1)明确TRPV6通道在胰腺癌细胞体外增殖、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；2)在体内阐明TRPV6通道在肿瘤生长和进展中的作用；3)在患者资料的回顾研究中，确定TRPV6通道的表达与肿瘤分级以及患者预后的相关性。作为本项目的基本部分，我们将第一个展示TRPV6通道在PDAC进展中的功能作用。我们的结果将进一步表明TRPV6通道是否可以在临床实践中用作诊断和/或预后工具。