Cited by 192Pancreatic and Hepatic Oncology ResearchCancer, Lipids, and MetabolismProtein Kinase Regulation and GTPase Signaling

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Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism

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Patra, Krushna C., Kato, Yasutaka, Mizukami, Yusuke, Widholz, Sebastian, Boukhali, Myriam, Revenco, Iulia, Grossman, Elizabeth A., Ji, Fei, Sadreyev, Ruslan I., Liss, Andrew S., Screaton, Robert A., Sakamoto, Kei, Ryan, David P., Mino-Kenudson, Mari, Castillo, Carlos Fernandez-del, Nomura, Daniel K., Haas, Wilhelm, Bardeesy, Nabeel·2018·Nature Cell Biology

DOI 10.1038/s41556-018-0122-3PMC PMC6044476

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Abstract

G protein α s (GNAS) mediates receptor-stimulated cAMP signalling, which integrates diverse environmental cues with intracellular responses. GNAS is mutationally activated in multiple tumour types, although its oncogenic mechanisms remain elusive. We explored this question in pancreatic tumourigenesis where concurrent GNAS and KRAS mutations characterize pancreatic ductal adenocarcinomas (PDAs) arising from intraductal papillary mucinous neoplasms (IPMNs). By developing genetically engineered mouse models, we show that Gnas R201C cooperates with Kras G12D to promote initiation of IPMN, which progress to invasive PDA following Tp53 loss. Mutant Gnas remains critical for tumour maintenance in vivo. This is driven by protein-kinase-A-mediated suppression of salt-inducible kinases (Sik1-3), associated with induction of lipid remodelling and fatty acid oxidation. Comparison of Kras-mutant pancreatic cancer cells with and without Gnas mutations reveals striking differences in the functions of this network. Thus, we uncover Gnas-driven oncogenic mechanisms, identify Siks as potent tumour suppressors, and demonstrate unanticipated metabolic heterogeneity among Kras-mutant pancreatic neoplasms.

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Authors: Patra, K. C., Kato, Y., Mizukami, Y., Widholz, S., Boukhali, M., Revenco, I., Grossman, E. A., Ji, F., Sadreyev, R. I., Liss, A. S., Screaton, R. A., Sakamoto, K., Ryan, D. P., Mino-Kenudson, M., Castillo, C. F.-D., Nomura, D. K., Haas, W., & Bardeesy, N.
Affiliations: Harvard University (US)
Massachusetts General Hospital (US)
Asahikawa Medical University (JP)
University of California, Berkeley (US)
University of Toronto (CA)
University of Dundee (GB)
Corresponding author: Bardeesy, Nabeel
ORCID: Patra, Krushna C.
Kato, Yasutaka
Mizukami, Yusuke
Widholz, Sebastian
Boukhali, Myriam
Revenco, Iulia
Ji, Fei
Sadreyev, Ruslan I.
Liss, Andrew S.
Screaton, Robert A.
Sakamoto, Kei
Ryan, David P.
Mino-Kenudson, Mari
Nomura, Daniel K.
Haas, Wilhelm
Bardeesy, Nabeel
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2018-06-25
Volume: 20
Issue: 7
Pages: 811-822
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/s41556-018-0122-3
PMC: PMC6044476
OpenAlex: W2809279418
Cited by: 192
References: 70
Citations by year: 2026: 10 · 2025: 35 · 2024: 31 · 2023: 29 · 2022: 21 · 2021: 28 · 2020: 14 · 2019: 19 · 2018: 5
FWCI: 6.19
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Japan Society for the Promotion of Science (17K09472)
National Cancer Institute (P50CA127003, R01CA133557, P01CA117969)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: GNAS, pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasm, KRAS G12D, cAMP signaling, protein kinase A, salt-inducible kinases, lipid remodeling, fatty acid oxidation, cancer metabolism, p53 deficiency, tumour suppressor, oncogenic mechanisms
MeSH terms: Animals, Cell Transformation, Neoplastic, Chromogranins, Enzyme Repression, Fatty Acids, Female, Humans, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Mutation, Oxidation-Reduction, Pancreatic Neoplasms, Phenotype, Genes, ras, Time Factors, Tumor Cells, Cultured, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Mice, Inbred NOD, Protein Serine-Threonine Kinases, Cyclic AMP-Dependent Protein Kinases, GTP-Binding Protein alpha Subunits, Gs, Genetic Predisposition to Disease, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Lipid Metabolism, Mice, 129 Strain, Cellular Reprogramming

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Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism

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