Abstract 1249: Metabolomic analysis of a genetically defined model of oncogenesis reveals that common oncogenic mutations result in synergistic deregulation of multiple metabolic pathways

Oncogenesis induces profound changes to the cellular metabolic network. A number of these cancer-cell metabolic phenotypes have been found to be important for in vivo tumorigenesis. We have utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to globally profile the metabolic network of a genetically-defined experimental model of oncogenesis in an attempt to identify novel metabolic activities induced by transformation. Furthermore, we sought to delineate how common oncogenic mutations contribute to specific metabolic phenotypes. We have analyzed how dominant negative p53 and constitutively active Ras expression, either independently or in concert, impacts the metabolic activity of non-transformed parental colon crypt epithelial cells. In addition to measuring steady-state metabolite concentrations, we have employed isotope tracer analysis to measure the impact of oncogenic mutation on metabolic pathway kinetics. We find that combined p53 and Ras oncogenic mutation synergistically activates numerous aspects of central carbon metabolism including glycolysis, glutamine catabolism, and pyrimidine and purine biosynthesis. Our data indicate that many well-defined oncogenic metabolic phenotypes are the result of a cooperative effect of combinatorial mutation highlighting the importance of identifying the interaction between oncogenic signal transduction and metabolic regulation for understanding the etiology of the cancer-cell metabolic state. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1249. doi:10.1158/1538-7445.AM2011-1249