Differential Cell Susceptibilities to KrasG12D in the Setting of Obstructive Chronic Pancreatitis

Abstract Background and Aims Activating mutation of the KRASgene 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 KRASmutation is not known. Methods We used a mouse model to express an activating mutation of Krasin conjunction with obstruction of the main pancreatic ductto recapitulate a common etiology of human chronic pancreatitis. Because the cellof originof PDAC is not clear, Krasmutation was introduced into either duct cells or acinar cells. Results While KrasG12D 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 KRASG12D -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.