Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
复制标题
DOI：
10.1016/j.cell.2012.01.058
复制
发表时间：
2012-04-27
期刊：
影响因子：
64.5
通讯作者：
DePinho RA
中科院分区：
文献类型：
--
作者：
Ying H;Kimmelman AC;Lyssiotis CA;Hua S;Chu GC;Fletcher-Sananikone E;Locasale JW;Son J;Zhang H;Coloff JL;Yan H;Wang W;Chen S;Viale A;Zheng H;Paik JH;Lim C;Guimaraes AR;Martin ES;Chang J;Hezel AF;Perry SR;Hu J;Gan B;Xiao Y;Asara JM;Weissleder R;Wang YA;Chin L;Cantley LC;DePinho RA
肿瘤维持依赖于驱动癌基因的持续活动，尽管它们的限速作用高度依赖于背景。致癌性 Kras 突变是胰腺导管腺癌 (PDAC) 的标志性事件，在肿瘤发生中发挥关键作用。在此，诱导型 KrasG12D 驱动的 PDAC 小鼠模型表明，高级 PDAC 仍然严格依赖于 KrasG12D 表达。转录组和代谢组学分析表明，KrasG12D 通过刺激葡萄糖摄取并将葡萄糖中间体引导至己糖胺生物合成和磷酸戊糖途径 (PPP)，在控制肿瘤代谢方面发挥着至关重要的作用。这些研究还表明，致癌的 Kras 促进核糖生物发生。与经典模型不同，我们证明 KrasG12D 驱动糖酵解中间体进入非氧化性 PPP，从而将核糖生物发生与 NADP/NADPH 介导的氧化还原控制脱钩。总之，这项工作提供了关于致癌 Kras 如何促进天然肿瘤代谢重编程的体内机制见解，并阐明了可用于 PDAC 治疗益处的潜在代谢靶点。
Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on KrasG12D expression. Transcriptome and metabolomic analyses indicate that KrasG12D serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that KrasG12D drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC.
登录
查看更多内容
影响因子：
64.5
作者：
Clasquin MF;Melamud E;Singer A;Gooding JR;Xu X;Dong A;Cui H;Campagna SR;Savchenko A;Yakunin AF;Rabinowitz JD;Caudy AA
通讯作者：
Caudy AA
影响因子：
11.4
作者：
BOLSCHER, JGM;VANDERBIJL, MMW;PLOEGH, HL
通讯作者：
PLOEGH, HL
影响因子：
30.8
作者：
Kawaguchi, Y;Cooper, B;Wright, CVE
通讯作者：
Wright, CVE
DOI：
10.1073/pnas.0700690104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Funes, Juan M.;Quintero, Marisol;Boshoff, Chris
通讯作者：
Boshoff, Chris
影响因子：
2.9
作者：
Fujita, Hayato;Ohuchida, Kenoki;Tanaka, Masao
通讯作者：
Tanaka, Masao