Abstract A1-58: Revisiting cancer energetics: Establishing a link between altered fatty-acid metabolism and metastasis

Abstract

Abstract Identifying genetic alterations that drive metastatic transformation of cancer cells with enhanced invasiveness and stem cell-like properties is crucial for developing novel therapeutics. Reprogramming of cellular metabolism is an important hallmark of cancer that sustains uncontrolled growth and proliferation. While alterations resulting in elevated glucose uptake and switch to aerobic glycolysis (Warburg effect) have received much attention in recent years, the relevance of fatty-acid (FA) metabolism in cancer progression has remained unclear. Highly aggressive, metastatic tumors resemble stem cells at the genetic and physiological level, and recent studies have revealed a critical role of FA metabolism in providing energy and maintaining the undifferentiated state of stem cells. Moreover, obesity and concurrent elevation in FA levels has been linked to increased mortality rates in cancer patients. These observations raise the possibility of a multi-faceted link between increased availability of FA, altered FA metabolism and cancer progression. Here we investigated the changes in gene expression , mutations and copy number variations in primary and metastatic tumors using a literature-curated set of genes involved in regulating cellular FA uptake, lipogenesis, FA oxidation and the Warburg-effect. Using the pan-cancer TCGA dataset, we showed that >70% of FA oxidation and lipogenesis genes exhibit a significantly higher mutation frequency in metastatic tumors compared to primary tumors. Moreover, >40% of the genes involved in FA uptake showed a significant copy-number gain in metastatic tumors. Next, we performed an association analysis between the gene expression levels of FA metabolism and Warburg effect genes with markers of metastatic progression in the TCGA RNAseq datasets for breast, colorectal, kidney, liver, lung, ovarian and prostate cancers. To score the metastatic potential of individual tumors, we assigned a previously established epithelial-mesenchymal transition gene signature score (EMT score) and then identified a set of co-expressed FA-metabolism genes in each cancer type that shared a concordant association with EMT score. Next, we applied a regression modeling approach utilizing the FA metabolism and Warburg-effect genes to predict the aggressiveness of tumors in each cancer type. We further demonstrated the ability of the gene signature derived from the regression model to accurately predict the aggressiveness of tumors in independent gene expression datasets. Our study established a metabolic gene signature that can predict metastatic potential and may serve as putative therapeutic targets for aggressive tumors. Importantly, this work highlights the crucial association of genetic alterations in FA metabolism with metastasis. Citation Format: Aritro Nath, Christina Chan. Revisiting cancer energetics: Establishing a link between altered fatty-acid metabolism and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-58.