Abstract SY22-03: Multi-omics analysis of paired normal and tumor tissues reveals when and what causes altered metabolism in colorectal cancer

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Abstract Metabolic reprogramming is a common hallmark of cancer. Most cancer cells produce ATP and the precursors of biomass (e.g., nucleotides, amino acids, and lipids) by shifting from oxidative phosphorylation to aerobic glycolysis, commonly known as the “Warburg effect.” Recently these cancer-specific metabolic pathways have been considered as attractive targets for cancer therapy. However, the mechanisms underlying the control of cancer cell metabolism are poorly understood. To address underlying mechanisms that induce metabolic reprogramming of cancer metabolism, we applied capillary electrophoresis mass spectrometry (CE-MS) metabolic profiling to paired normal tissues and tumor tissues obtained from 275 patients with colon cancer. Significant changes in the levels of many metabolites were observed between normal and tumor tissues. Unexpectedly, metabolite levels altered quite early and remained unchanged among cancer stages. S-Adenosylmethionine (SAM) was the most increased metabolite. Glucose was the second most decreased metabolite in tumor tissues, whereas lactate, the final product of glycolysis, was increased, which indicates activation of glycolysis (the Warburg effect). We then applied transcriptome analysis to paired normal-cancer colon tissues and revealed that alterations in mRNA levels also occurred at the adenoma stage. Regarding energy metabolism, mRNAs encoding glycolysis purine/pyrimidine synthesis, one-carbon metabolism, and fatty acid synthesis were highly expressed, whereas those in fatty acid oxidation were down-regulated in tumor tissue. Colon cancer is associated with mutations in oncogenes and tumor suppressor genes such as adenomatous polyposis coli (APC), Kirsten-ras (KRAS), and TP53. We applied next-generation sequencing technologies for the detection of somatic mutations to the tumor tissues and found mutation frequencies of 78% in APC, 68% in TP53, and 48% in KRAS. Similar to metabolome and transcriptome data, these mutations were umbiased among cancer stages. We investigated whether gene mutations including APC, KRAS, and TP53 mutations affected metabolism. Regardless of the presence or absence of the mutations, the levels of most metabolites were unaltered in tumor tissues. This raises the question of which molecules contribute to the regulation of metabolic reprogramming of colorectal cancer metabolism. Citation Format: Tomoyoshi Soga. Multi-omics analysis of paired normal and tumor tissues reveals when and what causes altered metabolism in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY22-03. doi:10.1158/1538-7445.AM2017-SY22-03