Acvr1bloss promotes formation of precancerous lesions from acinar and ductal cells of origin

Abstract

AbstractObjectivePancreatic ductal adenocarcinoma (PDAC) can develop from precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN), mucinous cystic neoplasm (MCN), and intraductal papillary mucinous neoplasm (IPMN), with IPMN having a more favorable prognosis. Previous studies indicated that loss ofAcvr1baccelerates the development of Kras-induced IPMN in the mouse pancreas, however, the cell type predominantly affected by these genetic changes remains unclear.DesignWe investigated the contribution of cellular origin by inducing IPMN associated mutations–KRASG12Dexpression andAcvr1bloss specifically in acinar (Ptf1aCreER;KrasLSL-G12D;Acvr1bfl/flmice) or ductal (Sox9CreER;KrasLSL-G12D;Acvr1bfl/flmice) cells in mice. We then performed MRI imaging and a thorough histopathological analysis of their pancreatic tissues.ResultsThe loss ofAcvr1bincreased the risk of developing PanIN from cells with a Kras mutation. This was more pronounced in the context of acinar cells, which progressed faster and formed cysts that developed into IPMN and tumors. Ductal cells developed fewer PanIN lesions, and progressed less frequently into cysts, but were associated with dilation of the main pancreatic duct. Immunohistochemistry revealed that lesions arising from both cell types exhibited features of gastric or pancreatobiliary epithelium. The caerulein treatment further accelerated the development of IPMN from acinar cells with mutant Kras and loss ofAcvr1b,but had no effect in ductal cells.ConclusionThese findings indicate that loss ofAcvr1bin the presence of the Kras oncogene promotes the development of precancerous lesions from both ductal and acinar cells, with lesions being more prevalent from acinar cells. Our study underscores the significance of the cellular context in the initiation and progression of precursor lesions from adult exocrine cells.