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

• Published in: Nature cell biology Vol. 20; no. 7; pp. 811 - 822
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2018; Nature Publishing Group
• Subjects: 38/77; 42/41; 42/44; 631/67/2327; 631/80/86; 631/80/86/2365; 64; 64/60; 82/58; 96/1; 96/106; 96/95; Animal models; Animals; Biomedical and Life Sciences; Cancer cells; Cancer Research; Carcinoma, Pancreatic Ductal - enzymology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Cell Biology; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellular Reprogramming - genetics; Cellular signal transduction; Chromogranins - genetics; Chromogranins - metabolism; Cyclic adenosine monophosphate; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Development and progression; Developmental Biology; Enzyme Repression; Fatty acids; Fatty Acids - metabolism; Female; G proteins; Gene Expression Regulation, Neoplastic; Genes, ras; Genetic aspects; Genetic engineering; Genetic Predisposition to Disease; Genetically modified organisms; GTP-Binding Protein alpha Subunits, Gs - genetics; GTP-Binding Protein alpha Subunits, Gs - metabolism; Heterogeneity; Humans; Intracellular signalling; Invasiveness; K-Ras protein; Kinases; Life Sciences; Lipid metabolism; Lipid Metabolism - genetics; Male; Metabolism; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Mutant Strains; Mice, Transgenic; Mutants; Mutation; Neoplasms; Oxidation; Oxidation-Reduction; Oxidation-reduction reactions; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phenotype; Physiological aspects; Protein kinase A; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein turnover; Proteins; Signal Transduction; Stem Cells; Suppressors; Time Factors; Tumor Cells, Cultured; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors; United States
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0122-3

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.
Bardeesy and colleagues show that mutant GNAS suppresses salt-inducible kinases by activating PKA, leading to lipid remodelling and pancreatic tumourigenesis