[HTML][HTML] Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism

H Ying, AC Kimmelman, CA Lyssiotis, S Hua, GC Chu… - Cell, 2012 - cell.com
H Ying, AC Kimmelman, CA Lyssiotis, S Hua, GC Chu, E Fletcher-Sananikone, JW Locasale
Cell, 2012cell.com
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 …
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 KrasG12D-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.
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