Differential Cell Susceptibilities to Kras in the Setting of Obstructive Chronic Pancreatitis

Background and Aims Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC) but how it synergizes with KRAS mutation is not known. Methods We used a mouse model to express an activating mutation of Kras in conjunction with obstruction of the main pancreatic duct to recapitulate a common etiology of human chronic pancreatitis. Because the cell of origin of PDAC is not clear, Kras mutation was introduced into either duct cells or acinar cells. Results While Kras G12D expression in both cell types was protective against damage-associated cell death, chronic pancreatitis induced p53, p21, and growth arrest only in acinar-derived cells. Mutant ducts cells did not elevate p53 or p21 expression and exhibited increased proliferation driving the appearance of PDAC over time. Conclusions One mechanism by which tissues may be susceptible or resistant to KRAS G12D -initiated tumorigenesis is whether or not they undergo a p53-mediated damage response. In summary, we have uncovered a mechanism by which inflammation and intrinsic cellular programming synergize for the development of PDAC.