GNASR201C Induces Pancreatic Cystic Neoplasms in Mice That Express Activated KRAS by Inhibiting YAP1 Signaling
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Background & aims Mutations at hotspots in GNAS, which encodes stimulatory G-protein, α subunits, are detected in approximately 60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We generated mice with KRAS-induced IPMNs that also express a constitutively active form of GNAS in pancreas and studied tumor development.Methods We generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras;Gnas mice); pancreatic tissues of these mice express activated KRAS and also express a mutant form of GNAS (GNAS R201C) upon doxycycline administration. Mice that were not given doxycycline were used as controls, and survival times were compared by Kaplan-Meier analysis. Pancreata were collected at different time points after doxycycline administration and analyzed by histology. Pancreatic ductal adenocarcinomas (PDACs) were isolated from mice and used to generate cell lines, which were analyzed by reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and colony formation and invasion assays. Full-length and mutant forms of yes-associated protein (YAP) were expressed in PDAC cells. IPMN specimens were obtained from 13 patients with IPMN undergoing surgery and analyzed by immunohistochemistry.Results All Kras;Gnas mice developed pancreatic cystic lesions that resemble human IPMNs; the grade of epithelial dysplasia increased with time. None of the control mice developed cystic lesions. Approximately one third of Kras;Gnas mice developed PDACs at a median of 30 weeks after doxycycline administration, whereas 33% of control mice developed PDACs. Expression of GNAS R201C did not accelerate the development of PDACs compared with control mice. However, the neoplasms observed in Kras;Gnas mice were more differentiated, and expressed more genes associated with ductal phenotypes, than in control mice. PDACs isolated from Kras;Gnas mice had activation of the Hippo pathway; in cells from these tumors, phosphorylated YAP1 was sequestered in the cytoplasm, and this was also observed in human IPMNs with GNAS mutations. Sequestration of YAP1 was not observed in PDAC cells from control mice.Conclusions In mice that express activated KRAS in the pancreas, we found expression of GNAS R201C to cause development of more differentiated tumors, with gene expression pattern associated with the ductal phenotype. Expression of mutant GNAS caused phosphorylated YAP1 to be sequestered in the cytoplasm, altering tumor progression.
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More recent IPMN mouse models that genocopy recurrent driver alterations (Kras, Gnas, Rnf43) demonstrate stepwise progression comparable to patient-derived IPMNs.
“More recent IPMN models have been generated that genocopy recurrent driver alterations observed in cognate human lesions (i.e. Kras, Gnas, Rnf43) (Fig 1)34–36, and these models demonstrate the comparable stepwise progression observed in patient derived IPMNs.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [34]
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Molecular Pathology of Pancreatic Cystic Lesions with a Focus on Malignant Progression
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Clinical and Molecular Attributes and Evaluation of Pancreatic Cystic Neoplasm
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Cholesterol Activates Cyclic AMP Signaling in Metaplastic Acinar Cells
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Recent insight into the role and therapeutic potential of YAP/TAZ in gastrointestinal cancers
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Active Gα i/o Mutants Accelerate Breast Tumor Metastasis via the c-Src Pathway
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Going Rogue: Mechanisms, Regulation, and Roles of Mutationally Activated Gα in Human Cancer
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Self-citationIntraductal Papillary Mucinous Neoplasms: Attack of the Clones
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Self-citation
- Authors
- Ideno, N., Yamaguchi, H., Ghosh, B., Gupta, S., Okumura, T., Steffen, D. J., Fisher, C. G., Wood, L. D., Singhi, A. D., Nakamura, M., Gutkind, J. S., & Maitra, A.
- Affiliations
- University of California San Diego (US)
- University of Pittsburgh (US)
- Kyushu University (JP)
- Corresponding author
- Ideno, Noboru
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 155
- Issue
- 5
- Pages
- 1593-1607.e12
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6219919
- OpenAlex
- W2888633597
- Cited by
- 80
- References
- 48
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 13 · 2023: 9 · 2022: 12 · 2021: 14 · 2020: 9 · 2019: 8 · 2018: 2
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Uehara Memorial Foundation
- National Cancer Institute (CA200468, CA218004, CA196403)
- Cancer Prevention and Research Institute of Texas
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS G12D, pancreatic cystic neoplasms, intraductal papillary mucinous neoplasm, pancreatic ductal adenocarcinoma, YAP, Hippo signaling pathway, epithelial dysplasia, tumor differentiation
- MeSH terms
- YAP-Signaling Proteins, Animals, Chromogranins, Humans, Mutation, Pancreatic Neoplasms, Phosphoproteins, Signal Transduction, Proto-Oncogene Proteins p21(ras), Neoplasms, Cystic, Mucinous, and Serous, Cell Cycle Proteins, GTP-Binding Protein alpha Subunits, Gs, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Mice
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