@article{aa09d773886943b19d05d3286ade2d00,
title = "Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism",
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.",
author = "Haoqiang Ying and Kimmelman, {Alec C.} and Lyssiotis, {Costas A.} and Sujun Hua and Chu, {Gerald C.} and Eliot Fletcher-Sananikone and Locasale, {Jason W.} and Jaekyoung Son and Hailei Zhang and Coloff, {Jonathan L.} and Haiyan Yan and Wei Wang and Shujuan Chen and Andrea Viale and Hongwu Zheng and Paik, {Ji Hye} and Carol Lim and Guimaraes, {Alexander R.} and Martin, {Eric S.} and Jeffery Chang and Hezel, {Aram F.} and Perry, {Samuel R.} and Jian Hu and Boyi Gan and Yonghong Xiao and Asara, {John M.} and Ralph Weissleder and Wang, {Y. Alan} and Lynda Chin and Cantley, {Lewis C.} and Depinho, {Ronald A.}",
note = "Funding Information: We thank Christopher Wright for the p48-Cre mice; Shan Zhou and Shan Jiang for expert monitoring of the mouse colony; Yingchun Liu, Yuxiang Zheng, Ning Wu, Alexandra Grassian, Joan Brugge, Min Yuan, and Susanne Breitkopf for helpful suggestions and technical support. Grant support derives from NIH grants T32 CA009382-26 (H.Y.) and P01 CA117969 (R.W., L.C., L.C.C., R.A.D.). Imaging was supported by U24 CA092782 and P50 CA86355 (R.W.). Mass spectrometry was supported by 5P01CA120964-05 (L.C.C. and J.A.), 5P30CA006516-46 (J.A.), and the BIDMC Research Capital Fund. A.C.K. is supported by the National Cancer Institute Grant R01 CA157490, Kimmel Scholar Award and AACR-PanCAN Career Development Award. C.A.L. is the Amgen Fellow of the Damon Runyon Cancer Research Foundation (DRG-2056-10). S.H. is supported by a Damon Runyon Fellowship. A.C.K. is a Consultant for Forma Therapeutics. L.C.C. is a founder of Agios Pharmaceuticals, a company developing drugs to target metabolic enzymes for cancer therapy. ",
year = "2012",
month = apr,
day = "27",
doi = "10.1016/j.cell.2012.01.058",
language = "English (US)",
volume = "149",
pages = "656--670",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}