Differential cell susceptibilities to Kras in the setting of obstructive chronic pancreatitis
- PMID: 31310834 [PubMed].
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 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-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.