GnasR201C Induces Murine Pancreatic Cystic Neoplasms through Suppression of YAP1 Signaling and Transcriptional Reprogramming

Ideno, N.; Yamaguchi, H.; Ghosh, B.; Gupta, S.; Okumura, T.; Fisher, C. G.; Wood, L. D.; Singhi, A. D.; Nakamura, M.; Gutkind, J. S.; Maitra, A.

doi:10.1101/310292

bioRxiv · 10.1101/310292

GnasR201C Induces Murine Pancreatic Cystic Neoplasms through Suppression of YAP1 Signaling and Transcriptional Reprogramming

Ideno, N.·Yamaguchi, H.·Ghosh, B.·Gupta, S.·Okumura, T.·Fisher, C. G.·Wood, L. D.·Singhi, A. D.·Nakamura, M.·Gutkind, J. S.·Maitra, A.

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Abstract

Background & AimsSomatic \"hotspot\" mutations of GNAS, which encodes for the alpha subunit of stimulatory G-protein, are present in ~60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. There are currently no cognate animal models that recapitulate the biology of mutant Gnas-induced IPMNs, and the underlying mechanisms that lead to the cystic pathway of neoplasia in the pancreas remain unknown.\n\nMethodsWe generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras; Gnas mice) where pancreas-specific GnasR201C expression was induced by doxycycline administration. In this model, mutant Kras is constitutively expressed, and control mice were produced through absence of doxycycline. Separate cohorts of mice were utilized for timed necropsies and for Kaplan-Meier survival analysis. Isogenic cell lines (with doxycycline inducible mutant Gnas expression) were propagated from the resulting pancreatic ductal adenocarcinoma (PDAC).\n\nResultsCo-expression of KrasG12D and GnasR201C resulted in the development of pancreatic cystic lesions resembling human IPMNs in 100% of mice, with higher grades of epithelial dysplasia observed over time. Approximately one-third of Kras; Gnas mice developed PDAC at a median of 38 weeks post doxycycline induction. GnasR201C did not accelerate oncogenic transformation with KrasG12D, but rather, reprogrammed Ras-induced neoplasms towards a well-differentiated phenotype. GnasR201C induction led to activation of the inhibitory Hippo kinase cascade and cytoplasmic sequestration of phosphorylated YAP1 protein, a phenomenon that was also observed in human IPMN with GNAS mutations.\n\nConclusionsGNASR201C functions not as a traditional oncogene, but rather as an \"oncomodulator\" of KRAS-mediated pancreatic neoplasia, through suppression of YAP1 and transcriptional reprogramming towards a differentiated (large ductal) phenotype.

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Ideno, N., Yamaguchi, H., Ghosh, B., Gupta, S., Okumura, T., Fisher, C. G., Wood, L. D., Singhi, A. D., Nakamura, M., Gutkind, J. S., Maitra, A.. 2018-04-28. GnasR201C Induces Murine Pancreatic Cystic Neoplasms through Suppression of YAP1 Signaling and Transcriptional Reprogramming. https://doi.org/10.1101/310292

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