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Background 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. Objective Combining a recently developed mouse model of CP carrying the human carboxypeptidase A1 ( CPA1 ) p.N256K mutation with the established Kras G12D pancreatic cancer model, we characterised mechanisms linking chronic inflammation to early pancreatic carcinogenesis. Design We crossed Cpa1 N256K mice (Cpa1) with Ptf1a Cre ;Kras LSL-G12D (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. Results KC-Cpa1 pancreata displayed a stark increase in remodelling, fibrosis and formation of metaplastic lesions as compared with KC. Cpa1 N256K 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. Conclusions The humanised KC-Cpa1 mouse model reveals the interplay of inflammation in hereditary CP and carcinogenesis. Cpa1 N256K -induced plasticity in acinar and ductal cells, inflammation and cell-cell interaction networks cooperate with Kras G12D in early pancreatic carcinogenesis.
Inamdar et al. (Fri,) studied this question.