Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism
Menée sur un modèle murin, cette étude met en évidence un mécanisme de nature métabolique par lequel l'expression du gène Kras favorise la croissance d'un adénocarcinome canalaire du pancréas
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. º Oncogenic KrasG12D is required for PDAC tumor maintenance º KrasG12D reprograms PDAC metabolism by stimulating glucose uptake and glycolysis º KrasG12D drives enhanced glycolytic flux into glycosylation and ribose biogenesis º This metabolic shift is mediated by MEK activation and Myc-dependent transcription Pancreatic cancers are frequently associated with activated Kras, which is now shown in a genetically engineered mouse model to reprogram tumor metabolism by channeling glucose into several biosynthetic pathways critical for tumor growth and maintenance.
Cell 2012