Haoqiang Ying 1 , 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 Chang , Aram 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
Apr 27 2012
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.