Misfolding CPA1 mutation accelerates precancerous pancreas lesions in KC mice

Germline mutations in the CPA1 gene encoding carboxypeptidase A1 were found in association with chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). The mutations increase pancreatic disease risk, presumably, by causing proenzyme misfolding and endoplasmic reticulum stress. Previously, we showed that CPA1 N256K mice that carry the p.N256K misfolding human CPA1 mutation in the mouse Cpa1 gene develop spontaneous chronic pancreatitis. Here, our aim was to investigate whether CPA1 N256K mice have increased susceptibility to PDAC induced by a Kras mutation. We generated Kras^LSL-G12D × p48-Cre (KC) and Kras^LSL-G12D × p48-Cre × CPA1 N256K (KC-CPA1) mice and compared the development of pancreas pathology in the two strains at 1, 3, 6, and 12 mo of age. We observed progressive parenchymal remodeling in both strains, with more rapid changes in KC-CPA1 mice. Thus, histological analysis revealed loss of normal pancreas parenchyma, extensive fibrosis, and aberrant ductal structures such as acinar-to-ductal metaplasia and precancerous pancreatic intraepithelial neoplasia. At 3 mo, these microscopic changes were significantly more abundant in KC-CPA1 versus KC mice. Owing to the massive fibrosis, the pancreas weight of KC and KC-CPA1 mice was significantly increased relative to C57BL/6N and CPA1 N256K controls, with the largest increase observed in 3-mo-old KC-CPA1 animals. The observations indicate that a misfolding Cpa1 mutation accelerated the development of precancerous lesions and fibro-inflammatory remodeling in the pancreas of KC mice, providing support for the notion that CPA1 mutations might be risk factors for human PDAC.NEW & NOTEWORTHY Inborn mutations in the CPA1 gene encoding carboxypeptidase A1 have been proposed to increase the risk of pancreatic ductal adenocarcinoma (PDAC) by causing enzyme misfolding and endoplasmic reticulum stress in the pancreas. Here, we demonstrated in a novel mouse model that a misfolding Cpa1 mutation accelerated the development of precancerous lesions driven by mutant Kras in the pancreas. The observations offer experimental support for the notion that CPA1 mutations are risk factors for human PDAC.