Lara Magni:
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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, with a 5-years survival rate below 10%. The late diagnosis and the failure of current treatments remain the most important challenges to overcome and therefore, novel biomarkers and therapeutic targets are urgently needed to increase the chances of survival for patients. The PDAC tumor microenvironment (TME) is a solid and fibrotic area that contributes to cancer development and to the failure of radio and chemotherapy. TME is composed of cellular and non-cellular elements, including extracellular ATP (eATP), cytokines, growth factors and collagen. In particular, eATP is considered to be high in the TME and this leads to the activation of purinergic signaling. One of the purinergic receptors of interest in PDAC is P2X7R. It is encoded by a highly polymorphic gene resulting in several splice variants and SNPs, some of which associated with several pathologies. P2X7R is expressed in pancreatic stellate cells (PSCs), cancer cells and immune cells. Recent studies showed its involvement in pancreatic cancer cell survival, invasion and migration as well as PSCs survival.
In this study, we showed that PSCs and cancer cells contribute to the release of ATP in the TME, after different types of stimulation (study 1). Moreover, with presumed high concentration of eATP in TME, the activation of P2X7R in PSCs favors the release of IL-6, which in turn activates the IL- 6R-STAT3 pathway in cancer cells, promoting cancer progression. Further, we showed that two P2X7R SNPs, Gly150Arg and Arg276His variants, are associated with different risk of developing PDAC, one protective and one promoting, respectively (study 2). The expression of these variants in PSCs and cancer cells reveals a different cellular behavior with clear opposite effects on Ca2+ signals and cancer migration after stimulation with the P2X7R agonist BzATP, as well as differences in dye uptake. In the given conditions, these results indicated Gly150Arg to be a LOF receptor while Arg276His receptor showed diverse responses in the different assays and will therefore require further analysis. In conclusion, the research presented in this thesis provides novel insights on the role of P2X7R in PDAC and ascribes this receptor as a possible therapeutic target as well as a novel biomarker in PDAC.