Hereditary chronic pancreatitis induced plasticity cooperates with mutant Kras in early pancreatic carcinogenesis.

Abstract

Chronic pancreatitis (CP) is a risk factor for pancreatic cancer, with inherited cases conferring a markedly increased risk. The underlying mechanisms driving malignant transformation by CP remain poorly understood. Combining a recently developed mouse model of CP carrying the human carboxypeptidase A1 (<i>CPA1</i>) p.N256K mutation with the established <i>Kras^G12D</i> pancreatic cancer model, we characterised mechanisms linking chronic inflammation to early pancreatic carcinogenesis. We crossed <i>Cpa1</i> ^<i>N256K</i> mice (Cpa1) with <i>Ptf1a^Cre;Kras^LSL-G12D</i> (KC). In Cre, Cpa1, KC and KC-Cpa1 mice, we performed phenotypical characterisation at five early time points and in an ageing cohort. Assessment of histology combined with both RNA-sequencing and single-cell RNA-sequencing was performed to analyse metaplasia, preneoplastic lesions and cellular heterogeneity. KC-Cpa1 pancreata displayed a stark increase in remodelling, fibrosis and formation of metaplastic lesions as compared with KC. <i>Cpa1^N256K</i> induced extensive plasticity in both the acinar and ductal compartment, including an early acinar-to-ductal metaplasia state in acinar cells characterised by an upregulation of endoplasmic reticulum stress markers and an inflammatory ductal phenotype (iDucts). We characterised the complex cell-cell communication networks underlying both pancreatic inflammation and early carcinogenesis, revealing disease-specific signalling between ductal cells, granulocytes and fibroblasts. The humanised KC-Cpa1 mouse model reveals the interplay of inflammation in hereditary CP and carcinogenesis. <i>Cpa1^N256K</i> -induced plasticity in acinar and ductal cells, inflammation and cell-cell interaction networks cooperate with <i>Kras^G12D</i> in early pancreatic carcinogenesis.