Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism

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• 作者：Haoqiang Ying¹ ; ² ; ¹⁵ ; Alec&#160 ; C. Kimmelman³ ; ¹⁵ ; ^{alec_kimmelman@dfci.harvard.edu} ; Costas&#160 ; A. Lyssiotis⁴ ; ⁸ ; ¹⁵ ; Sujun Hua¹ ; ² ; Gerald&#160 ; C. Chu¹ ; ² ; ⁹ ; Eliot Fletcher-Sananikone¹ ; ² ; Jason&#160 ; W. Locasale⁴ ; ⁸ ; Jaekyoung Son³ ; Hailei Zhang¹ ; Jonathan&#160 ; L. Coloff⁵ ; Haiyan Yan¹ ; ² ; Wei Wang¹ ; ² ; ¹⁰ ; Shujuan Chen¹ ; Andrea Viale¹ ; ² ; Hongwu Zheng¹ ; ² ; Ji-hye Paik¹ ; ² ; Carol Lim¹ ; ² ; Alexander&#160 ; R. Guimaraes¹² ; Eric&#160 ; S. Martin¹ ; ² ; Jeffery Chang¹ ; ² ; Aram&#160 ; F. Hezel¹ ; ² ; Samuel&#160 ; R. Perry¹ ; ² ; Jian Hu¹ ; ² ; Boyi Gan¹ ; ² ; Yonghong Xiao¹ ; John&#160 ; M. Asara⁶ ; ⁸ ; Ralph Weissleder⁴ ; ¹² ; Y.&#160 ; Alan Wang¹ ; ² ; Lynda Chin¹ ; ² ; ¹¹ ; ¹³ ; Lewis&#160 ; C. Cantley⁴ ; ⁸ ; Ronald&#160 ; A. DePinho¹ ; ² ; ⁷ ; ¹⁴ ; ^{rdepinho@mdanderson.org}
• 刊名：Cell
• 出版年：2012
• 期刊代码：50_00928674
• 类别：med
• 出版时间：27 April, 2012
• 卷：149
• 期：3
• 页码：656-670
• 文件大小：3136 K

摘要

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Summary

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聽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.