GNAS^R201C and KRAS^G12D Cooperate to Induce Cystic Pancreatic Lesions

Intraductal papillary mucinous neoplasms (IPMN) are benign, cystic precursor lesions in the pancreas that can potentially progress to malignant pancreatic ductal adenocarcinoma (PDAC). Having previously shown that almost all IPMNs harbor activating mutations in either KRAS or the alpha subunit of an adenylate cyclase-stimulating G protein (encoded by GNAS), Ideno and colleagues inducibly overexpressed mutant Gnas^R201C in a mouse model of Kras^G12D-driven pancreatic cancer to further elucidate the role of mutant Gnas in IPMN pathogenesis. Mutant Kras pancreata gave rise to pancreatic intraepithelial neoplasia (PanIN), which are the noncystic type of PDAC precursor lesions, whereas pancreata from all mutant Kras;Gnas mice harbored IPMNs; further, the prevalence of high-grade IPMNs in mutant Kras;Gnas mice was higher than that of high-grade PanINs in mutant Kras mice. Coexpression of mutant Gnas and Kras resulted in the formation of moderately differentiated PDAC that were locally invasive and increased MAPK activation, whereas mutant Kras mice harbored poorly differentiated PDAC that were more metastatic. Expression of mutant Gnas in cell lines established from mutant Kras;Gnas PDAC resulted in increased levels of cAMP, decreased soft-agar colony formation and invasion, and increased epithelial differentiation. Expression of Gnas repressed YAP1 signaling and cytoplasmic sequestration of YAP1, and YAP1 was localized to the nuclei of PanINs from mutant Kras mice and to the cytoplasm in IPMNs from mutant Kras;Gnas mice. Consistent with these findings, mutant Gnas expression or cAMP induction resulted in increased activation of the YAP1 suppressor LATS1 and expression of α-E-catenin, which is a negative regulator of YAP1 that has been implicated in epithelial differentiation. Moreover, cytoplasmic YAP1 was detected in mutant GNAS human IPMNs, whereas nuclear YAP1 expression was associated with wild-type GNAS human IPMNs. These results describe a mouse model of IPMN driven by concomitant overexpression of mutant Gnas and Kras that recapitulates the human disease and provide insight into the role of GNAS in the progression of IMPN to PDAC.

Ideno N, Yamaguchi H, Ghosh B, Gupta S, Okumura T, Steffen DJ, et al. GNAS^R201C induces pancreatic cystic neoplasms in mice that express activated KRAS by inhibiting YAP1 signaling. Gastroenterology 2018 Aug 22 [Epub ahead of print].

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