Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism.
Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism.
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DOI：
10.1038/s41556-018-0122-3
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发表时间：
2018-07
影响因子：
21.3
通讯作者：
Bardeesy N
中科院分区：
文献类型：
--
作者：
Patra KC;Kato Y;Mizukami Y;Widholz S;Boukhali M;Revenco I;Grossman EA;Ji F;Sadreyev RI;Liss AS;Screaton RA;Sakamoto K;Ryan DP;Mino-Kenudson M;Castillo CF;Nomura DK;Haas W;Bardeesy N
G蛋白αS(GNAS)介导受体刺激的cAMP信号，将多种环境信号与细胞内反应整合在一起。GNAS在多种肿瘤类型中被突变激活，尽管其致癌机制仍然难以捉摸。我们在胰腺肿瘤发生中探索了这一问题，其中同时存在GNAS和KRAS突变的胰腺导管腺癌(PDA)是由导管内乳头状粘液肿瘤(IPMN)引起的。通过建立基因工程小鼠模型，我们表明GNASR201C与KrasG12D合作促进IPMN的启动，IPMN在TP53丢失后进展为侵袭性PDA。突变-GNAS仍然是体内肿瘤维持的关键。这是由蛋白激酶A介导的抑制盐诱导的激酶(SIK1-3)驱动的，与诱导脂质重塑和脂肪酸氧化有关。对带有和不带有GNAS突变的KRAS突变的胰腺癌细胞进行比较，发现该网络的功能存在显著差异。因此，我们揭示了GNAS驱动的致癌机制，确定了SIKs是有效的肿瘤抑制因子，并证明了KRAS突变的胰腺肿瘤中未预料到的代谢异质性。
G-protein αs (GNAS) mediates receptor-stimulated cAMP signaling, which integrates diverse environmental cues with intracellular responses. GNAS is mutationally activated in multiple tumor types, although its oncogenic mechanisms remain elusive. We explored this question in pancreatic tumorigenesis 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 tumor maintenance in vivo. This is driven by protein kinase A-mediated suppression of salt-inducible kinases (SIK1-3), associated with induction lipid remodeling 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 tumor suppressors, and demonstrate unanticipated metabolic heterogeneity among KRAS-mutant pancreatic neoplasms.
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影响因子：
7.3
作者：
Amato, Eliana;dal Molin, Marco;Mafficini, Andrea;Yu, Jun;Malleo, Giuseppe;Rusev, Borislav;Fassan, Matteo;Antonello, Davide;Sadakari, Yoshihiko;Castelli, Paola;Zamboni, Giuseppe;Maitra, Anirban;Salvia, Roberto;Hruban, Ralph H.;Bassi, Claudio;Capelli, Paola;Lawlor, Rita T.;Goggins, Michael;Scarpa, Aldo
通讯作者：
Scarpa, Aldo
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.9
作者：
Collins, Meredith A.;Bednar, Filip;di Magliano, Marina Pasca
通讯作者：
di Magliano, Marina Pasca
影响因子：
7.3
作者：
Cheng H;Liu P;Wang ZC;Zou L;Santiago S;Garbitt V;Gjoerup OV;Iglehart JD;Miron A;Richardson AL;Hahn WC;Zhao JJ
通讯作者：
Zhao JJ