GNAS R201H and Kras G12D cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm

Intraductal papillary mucinous neoplasm (IPMN), the most common pancreatic cystic neoplasm, is known to progress to invasive ductal adenocarcinoma. IPMNs commonly harbor activating somatic mutations in GNAS and KRAS , primarily GNAS R201H and KRAS G12D . GNAS encodes the stimulatory G-protein α subunit (Gsα) that mediates a stimulatory signal to adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP), subsequently activating cAMP-dependent protein kinase A. The GNAS R201H mutation results in constitutive activation of Gsα. To study the potential role of GNAS in pancreatic tumorigenesis in vivo , we generated lines of transgenic mice in which the transgene consisted of Lox-STOP-Lox (LSL) - GNAS R201H under the control of the CAG promoter ( Tg(CAG-LSL-GNAS) ). These mice were crossed with pancreatic transcription factor 1a ( Ptf1a )-Cre mice ( Ptf1a Cre/+ ), generating Tg(CAG-LSL-GNAS) ; Ptf1a Cre/+ mice. This mouse line showed elevated cAMP levels, small dilated tubular complex formation, loss of acinar cells and fibrosis in the pancreas; however, no macroscopic tumorigenesis was apparent by 2 months of age. We then crossed Tg(CAG-LSL-GNAS) ; Ptf1a Cre/+ mice with LSL-Kras G12D mice, generating Tg(CAG-LSL-GNAS) ; LSL-Kras G12D ; Ptf1a Cre/+ mice. We used these mice to investigate a possible cooperative effect of GNAS R201H and Kras G12D in pancreatic tumorigenesis. Within 5 weeks, Tg(CAG-LSL-GNAS) ; LSL-Kras G12D ; Ptf1a Cre/+ mice developed a cystic tumor consisting of marked dilated ducts lined with papillary dysplastic epithelia in the pancreas, which closely mimicked the human IPMN. Our data strongly suggest that activating mutations in GNAS and Kras cooperatively promote murine pancreatic tumorigenesis, which recapitulates IPMN. Our mouse model may serve as a unique in vivo platform to find biomarkers and effective drugs for diseases associated with GNAS mutations.