Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism

被引：1579

作者：

Ying, Haoqiang ^{[2
,3
]}

Kimmelman, Alec C. ^{[1
]}

Lyssiotis, Costas A. ^{[4
,8
]}

Hua, Sujun ^{[2
,3
]}

Chu, Gerald C. ^{[2
,3
,9
]}

Fletcher-Sananikone, Eliot ^{[2
,3
]}

Locasale, Jason W. ^{[4
,8
]}

Son, Jaekyoung ^{[1
]}

Zhang, Hailei ^{[2
]}

Coloff, Jonathan L. ^{[5
]}

Yan, Haiyan ^{[2
,3
]}

Wang, Wei ^{[2
,3
,10
]}

Chen, Shujuan ^{[2
]}

Viale, Andrea ^{[2
,3
]}

Zheng, Hongwu ^{[2
,3
]}

Paik, Ji-hye ^{[2
,3
]}

Lim, Carol ^{[2
,3
]}

Guimaraes, Alexander R. ^{[12
]}

Martin, Eric S. ^{[2
,3
]}

Chang, Jeffery ^{[2
,3
]}

Hezel, Aram F. ^{[2
,3
]}

Perry, Samuel R. ^{[2
,3
]}

Hu, Jian ^{[2
,3
]}

Gan, Boyi ^{[2
,3
]}

Xiao, Yonghong ^{[2
]}

Asara, John M. ^{[6
,8
]}

Weissleder, Ralph ^{[4
,12
]}

Wang, Y. Alan ^{[2
,3
]}

Chin, Lynda ^{[2
,3
,11
,13
]}

Cantley, Lewis C. ^{[4
,8
]}

DePinho, Ronald A. ^{[2
,3
,7
,14
]}

机构：

[1] Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[4] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[8] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA

[9] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[10] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA

[11] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA

[12] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA

[13] Univ Texas MD Anderson Canc Ctr, Dept Med Genet, Houston, TX 77030 USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

来源：

CELL | 2012年 / 149卷 / 03期

关键词：

N-LINKED CARBOHYDRATE; K-RAS ADDICTION; CANCER; INDUCTION; MYC; EXPRESSION; BIOLOGY; PATHWAY; CELLS; MICE;

D O I：

10.1016/j.cell.2012.01.058

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) 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 Kras(G12D) 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.

引用

页码：656 / 670

页数：15

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