Abstract
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 GNASR201H and KRASG12D. 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 GNASR201H 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)-GNASR201H under the control of the CAG promoter (Tg(CAG-LSL-GNAS)). These mice were crossed with pancreatic transcription factor 1a (Ptf1a)-Cre mice (Ptf1aCre/+), generating Tg(CAG-LSL-GNAS);Ptf1aCre/+ 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);Ptf1aCre/+ mice with LSL-KrasG12D mice, generating Tg(CAG-LSL-GNAS);LSL-KrasG12D;Ptf1aCre/+ mice. We used these mice to investigate a possible cooperative effect of GNASR201H and KrasG12D in pancreatic tumorigenesis. Within 5 weeks, Tg(CAG-LSL-GNAS);LSL-KrasG12D;Ptf1aCre/+ 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.
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Acknowledgements
We are grateful to Dr David A Tuveson (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA) for providing LSL-KrasG12D mouse, Dr Takeshi Tanaka and Dr Emiko Hayama (Department of Pediatric Cardiology, Tokyo Women’s Medical University) for their work preparing the anti-Gsα antibody and Ms Yuko Fukuchi and Ms Michiyo Nakata (Institute of Resource Development and Analysis, Kumamoto University) for their technical assistance. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas, Ministry of Education, Culture, Sports, Science and Technology (26110003) to MO and a Grant-in-Aid for Challenging Exploratory Research, Japan Society for the Promotion of Science (24659167) to TF.
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Taki, K., Ohmuraya, M., Tanji, E. et al. GNASR201H and KrasG12D cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm. Oncogene 35, 2407–2412 (2016). https://doi.org/10.1038/onc.2015.294
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DOI: https://doi.org/10.1038/onc.2015.294
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