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

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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.