TY - JOUR

T1 - Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism

AU - Patra, Krushna C.

AU - Kato, Yasutaka

AU - Mizukami, Yusuke

AU - Widholz, Sebastian

AU - Boukhali, Myriam

AU - Revenco, Iulia

AU - Grossman, Elizabeth A.

AU - Ji, Fei

AU - Sadreyev, Ruslan I.

AU - Liss, Andrew S.

AU - Screaton, Robert A.

AU - Sakamoto, Kei

AU - Ryan, David P.

AU - Mino-Kenudson, Mari

AU - Castillo, Carlos Fernandez Del

AU - Nomura, Daniel K.

AU - Haas, Wilhelm

AU - Bardeesy, Nabeel

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048973113&partnerID=8YFLogxK

U2 - 10.1038/s41556-018-0122-3

DO - 10.1038/s41556-018-0122-3

M3 - Journal article

C2 - 29941929

AN - SCOPUS:85048973113

VL - 20

SP - 811

EP - 822

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 7

ER -