Format

Send to

Choose Destination
Nat Cell Biol. 2018 Jul;20(7):811-822. doi: 10.1038/s41556-018-0122-3. Epub 2018 Jun 25.

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

Author information

1
Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
2
Departments of Medicine, Harvard Medical School, Boston, MA, USA.
3
Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido, Japan.
4
Asahikawa Medical University, Hokkaido, Japan.
5
Departments of Nutritional Sciences and Toxicology, Chemistry, and Molecular and Cell Biology, University of California, Berkeley, CA, USA.
6
Departments of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
7
Department of Genetics, Harvard Medical School, Boston, MA, USA.
8
Departments of Pathology, Massachusetts General Hospital, Boston, MA, USA.
9
Department of Pathology, Harvard Medical School, Boston, MA, USA.
10
Sunnybrook Research Institute, Toronto, Ontario, Canada.
11
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
12
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Scotland, UK.
13
Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
14
Departments of Surgery, Massachusetts General Hospital, Boston, MA, USA.
15
Department of Surgery, Harvard Medical School, Boston, MA, USA.
16
Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu.
17
Departments of Medicine, Harvard Medical School, Boston, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu.

Abstract

G protein αs (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 GnasR201C cooperates with KrasG12D 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.

PMID:
29941929
PMCID:
PMC6044476
DOI:
10.1038/s41556-018-0122-3
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center