Inflammation-induced epithelial plasticity can be by-passed through Vps34 inactivation to limit pancreatic cancer initiation

International audience

English. Context Pancreatic ductal adenocarcinoma (PDAC) will become the second cause of cancer-related mortalities by 2030. PI3K/Akt/mTORC1 pathway is among the major oncogenic signaling pathways that are activated in PDAC. Whether class III PI3K also tightly control mTORC1 in physiological settings remains controversial; besides, the role of class III PI3-kinase remained underexplored both in PDAC and in pancreatitis, a potential risk factor for PDAC development. Class III PI3K comprises only one isoform named Vps34. Through its kinase activity, Vps34 plays a role in regulating autophagy. Autophagy is an evolutionarily conserved process, which plays an important function in both pancreatic physiology and pathophysiology. Methods In our study, we developed Vps34+/+, Vps34KI/KI(=V34), KC and KCVps34KI/KI (=KCV34) mice models to understand the role of class III of PI3-kinase in pancreatic diseases. Single-cell RNA sequence analysis, western blot analysis, immunofluorescence analysis and immunohistochemistry analysis were performed for collected tissues or acini cultured ex-vivo. Data were confirmed on Human samples.Results Vps34 inactivation in exocrine pancreas resulted in fibrogenesis and lipid accumulation. In vivo and ex vivo, acinar cells had heterogeneous levels of autophagy ; Vps34 inactivation showed blocked flux of autophagy and differential expression levels of autophagy-regulating proteins compared to WT acini. Autolysosome surface decreased in acinar cells with Vps34 inactivation. Surprisingly, despite a blockage of autophagy, those cells appeared resistant to mutant Kras oncogenicity as full inactivation of Vps34 in KC mice led to absence of precancer lesions in aged mice. ScRNA-seq showed that Vps34 inactivation prompted a selective loss of a subset of acinar cells with high mitochondrial and autophagy-related genes. Moreover, acinar cells with Vps34 inactivation showed enrichment in the expression of regenerating islet-derived 3 beta (Reg3b) gene. Acinar cells with Vps34 inactivation showed difference in Regs protein levels both at the basal levels and in response to autophagy modulators compared to WT acini. Finally, acinar cells with Vps34 inactivation showed also decreased levels of p-Akt levels, known to be necessary to pancreatic plasticity.Conclusion Vps34 full inactivation may protect from initiation of precancer lesions in the context of inflammation by bypassing epithelial plasticity. These finding may be a key to understand pancreatic cancer initiation.