Epithelial Nr5a2 heterozygosity cooperates with mutant Kras in the development of pancreatic cystic lesions.

Cystic neoplasms of the pancreas are an increasingly important public health problem. The majority of these lesions are benign but some progress to invasive pancreatic ductal adenocarcinoma (PDAC). There is a dearth of mouse models of these conditions. The orphan nuclear receptor NR5A2 regulates development, differentiation, and inflammation. Germline Nr5a2 heterozygosity sensitizes mice to the oncogenic effects of mutant Kras in the pancreas. Here, we show that - unlike constitutive Nr5a2+/- mice - conditional Nr5a2 heterozygosity in pancreatic epithelial cells, combined with mutant Kras (KPN+/- ), leads to a dramatic replacement of the pancreatic parenchyma with cystic structures and an accelerated development of high-grade PanINs and PDAC. Timed histopathological analyses indicated that in KPN+/- mice PanINs precede the formation of cystic lesions and the latter precede PDAC. A single episode of acute caerulein pancreatitis is sufficient to accelerate the development of cystic lesions in KPN+/- mice. Epithelial cells of cystic lesions of KPN+/- mice express MUC1, MUC5AC, and MUC6, but lack expression of MUC2, CDX2, and acinar markers, indicative of a pancreato-biliary/gastric phenotype. In accordance with this, in human samples we found a non-significantly decreased expression of NR5A2 in mucinous tumours, compared with conventional PDAC. These results highlight that the effects of loss of one Nr5a2 allele are time- and cell context-dependent. KPN+/- mice represent a new model to study the formation of cystic pancreatic lesions and their relationship with PanINs and classical PDAC. Our findings suggest that pancreatitis could also contribute to acceleration of cystic tumour progression in patients.