Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism

Haoqiang Ying, Alec C. Kimmelman, Costas A. Lyssiotis, Sujun Hua, Gerald C. Chu, Eliot Fletcher-Sananikone, Jason W. Locasale, Jaekyoung Son, Hailei Zhang, Jonathan L. Coloff, Haiyan Yan, Wei Wang, Shujuan Chen, Andrea Viale, Hongwu Zheng, Ji Hye Paik, Carol Lim, Alexander R. Guimaraes, Eric S. Martin, Jeffery ChangAram F. Hezel, Samuel R. Perry, Jian Hu, Boyi Gan, Yonghong Xiao, John M. Asara, Ralph Weissleder, Y. Alan Wang, Lynda Chin, Lewis C. Cantley, Ronald A. Depinho

Research output: Contribution to journalArticle

893 Scopus citations

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)656-670
Number of pages15
JournalCell
Volume149
Issue number3
DOIs
StatePublished - Apr 27 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., Yan, H., Wang, W., Chen, S., Viale, A., Zheng, H., Paik, J. H., Lim, C., Guimaraes, A. R., Martin, E. S., ... Depinho, R. A. (2012). Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell, 149(3), 656-670. https://doi.org/10.1016/j.cell.2012.01.058