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

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 KrasG12D pancreatic cancer model, we characterised mechanisms linking chronic inflammation to early pancreatic carcinogenesis.

DESIGN

We crossed Cpa1 N256K mice (Cpa1) with Ptf1aCre;KrasLSL-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. Cpa1N256K 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. Cpa1N256K -induced plasticity in acinar and ductal cells, inflammation and cell-cell interaction networks cooperate with KrasG12D in early pancreatic carcinogenesis.