Misfolding <i>CPA1</i> mutation accelerates precancerous pancreas lesions in <i>KC</i> mice

Germline mutations in the <i>CPA1</i> 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 <i>CPA1 N256K</i> mice that carry the p.N256K misfolding human <i>CPA1</i> mutation in the mouse <i>Cpa1</i> gene develop spontaneous chronic pancreatitis. Here, our aim was to investigate whether <i>CPA1 N256K</i> mice have increased susceptibility to PDAC induced by a <i>Kras</i> mutation. We generated <i>Kras^LSL-G12D</i> × <i>p48-Cre</i> (<i>KC</i>) and <i>Kras^LSL-G12D</i> × <i>p48-Cre</i> × <i>CPA1 N256K</i> (<i>KC-CPA1</i>) 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 <i>KC-CPA1</i> 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 <i>KC-CPA1</i> versus <i>KC</i> mice. Owing to the massive fibrosis, the pancreas weight of <i>KC</i> and <i>KC-CPA1</i> mice was significantly increased relative to C57BL/6N and <i>CPA1 N256K</i> controls, with the largest increase observed in 3-mo-old <i>KC-CPA1</i> animals. The observations indicate that a misfolding <i>Cpa1</i> mutation accelerated the development of precancerous lesions and fibro-inflammatory remodeling in the pancreas of <i>KC</i> mice, providing support for the notion that <i>CPA1</i> mutations might be risk factors for human PDAC.<b>NEW & NOTEWORTHY</b> Inborn mutations in the <i>CPA1</i> 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 <i>Cpa1</i> mutation accelerated the development of precancerous lesions driven by mutant <i>Kras</i> in the pancreas. The observations offer experimental support for the notion that <i>CPA1</i> mutations are risk factors for human PDAC.