Calcium dependent mechanisms of activation of pancreatic stellate cells: microenvironmental focus on PDAC invasion

现代医学的最新进展表明，许多病理实际上是离子通道病变（即离子通道结构和功能的改变）。癌症的发生也与这种离子通道畸变有关。事实上，在过去的十年中，肿瘤学研究中的一个新概念已经发展和推广，为肿瘤学的新篇章铺平了道路，创造了“肿瘤通道病”。尽管研究深入，胰腺导管腺癌（PDAC）仍然是最具侵袭性和难治性的癌症之一。对付这种疾病显然需要非常规的方法。是什么让PDAC在攻击性方面如此独特？我们解释这个谜题的关键假设是基于这样一个事实，即分泌胰管产生一个独特的离子间质微环境生态位，其中含有大量的细胞外基质（结缔组织增生），主要由间质胰星状细胞（PSC）分泌。PSCs参与细胞外基质（ECM）的转换。在胰腺癌的情况下，活化的PSCs在病理上分泌ECM导致纤维化，为治疗创造物理障碍。这种微环境有利于肿瘤早期侵袭性生长和转移。该项目的主要目标是解释微环境触发因素（机械应力、缺氧、分泌组）对调节胰腺癌细胞和间质细胞（如PSCs）细胞内Na+和Ca2+稳态的离子通道的影响。所获得的知识是必要的，以便了解由于微环境导致的PDAC进展的离子信号机制，并最终设计创新的、离子通道靶向的治疗策略，旨在使环境“正常化”并影响疾病轨迹。我们将使用创新的体外模型，实施探针来测量组织的物理化学特性，并在动物身上验证我们的假设。通过结合Albrecht Schwab的团队在迁移中机械敏感离子通道的作用方面的工作，以及Natalia Prevarskaya的团队在揭示离子通道调节的分子机制和概念方面的工作，该项目将允许对一个尚未被研究的领域提供新的视角：密切相连的Ca2+和Na+信号的微环境触发如何促进PDAC入侵。

Recent progress in modern medicine has shown that numerous pathologies are actually channelopathies (i.e. alterations in an ion channel’s structure and function). The development of cancers also involves such ion channel aberrations. Indeed, a new concept in oncological research has been developed and promoted over the last decade paving the way to a new chapter of oncology coined ‘Oncochannelopathies’. Despite intensive research, pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive and intractable cancers. Unconventional approaches are clearly needed to tackle the disease. What makes PDAC so singular in terms of aggressiveness? Our key hypothesis for the explanation of this enigma is based on the fact that the secretory pancreatic duct produces a unique ionic interstitial microenvironmental niche containing an abundant amount of extracellular matrix (desmoplasia) primarily secreted by stromal pancreatic stellate cells (PSC). PSCs are involved in extracellular matrix (ECM) turnover. In case of pancreatic cancer, activated PSCs pathologically secrete ECM leading to fibrosis, creating a physical barrier to therapy. This microenvironment is conducive to early invasive tumor growth and metastasis. The main goal of the project is to decipher the effect of microenvironmental triggers (mechanical stress, hypoxia, secretome) on ion channels regulating the intracellular Na+ and Ca2+ homeostasis in pancreatic cancer cells and stroma cells such as PSCs. The knowledge obtained is necessary in order to understand ionic signaling mechanisms underlying PDAC progression as a consequence of its microenvironment and eventually design innovative, ion channel targeted, therapeutic strategies aimed to “normalize” the environment and influence the disease trajectory. We will use innovative in vitro models, implementing probes to measure the physico-chemical properties of the tissue and validate our hypotheses in animals. By combining Albrecht Schwab's team that is recognized for the work on the role of mechanosensitive ion channels in migration, and Natalia Prevarskaya’s team that is known for its work on uncovering molecular mechanisms and concepts of ion channel regulation, this project will allow to shed new light on a yet poorly investigated domain: how microenvironmental triggers of the closely interconnected Ca2+ and Na+ signaling promote PDAC invasion.