Abstract 2448: Elucidating the metabolic plasticity of cancer by coupling gene regulation with metabolic pathways

Abstract

Abstract Metabolic plasticity allows cancer cells to adjust their metabolic phenotypes to grow and metastasize in hostile environments. Both glycolysis and oxidative phosphorylation (OXPHOS) are adapted by cancer cells to meet their bioenergetic and biosynthetic requirements in a context-dependent manner. Despite the advance in studies focusing only on glycolysis or OXPHOS in cancer, it remains largely unknown how cancer cells orchestrate different metabolic phenotypes for better survival. To address this question, there is an urgent need to develop systemic approaches to quantitatively study the interplay between glycolysis and OXPHOS in cancer. Mathematical modeling approaches have been employed to elucidate cancer metabolic reprogramming. Constraint-based models including flux balance analysis based on conservation of mass have been the most widely used approaches to simulate cancer metabolism. In addition, modeling efforts have also been developed to identify anomalous gene activity involved in cancer metabolism. These computational studies offer a quantitative and dynamical perspective of cancer metabolism mostly focusing on either metabolic pathways or gene activities. However, the alteration of the metabolic activity is often coupled with the change in gene activity, and vice versa. Thus, to comprehensively characterize cancer metabolic reprogramming, a mathematical modeling framework integrating gene regulation with metabolic pathways is urgently needed. Here, we establish a theoretical framework to elucidate cancer metabolic plasticity through systems biology analysis of the coupling of gene regulation and metabolic pathways. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis respectively, with the activities of three metabolic pathways: glucose oxidation, glycolysis and fatty acid oxidation (FAO). Guided by the model, we develop metabolic pathway signatures to quantify the activities of glycolysis, FAO and the citric acid cycle of tumor samples by evaluating the expression levels of enzymes involved in corresponding processes. The association of AMPK/HIF-1 activity with metabolic pathway activity, predicted by the model and verified by analyzing the well-annotated metabolomic and transcriptomic data from a breast cancer patients’ cohort, is further validated by in vitro studies of aggressive triple negative breast cancer cell lines. We further investigate the existence of an aggressive hybrid metabolic phenotype that enables cancer cells metabolic plasticity for better survival and a metabolically inactive phenotype that may be employed by cancer cells under pressure. To the best of our knowledge, we are the first, or at least one of the first, to couple gene regulation with metabolic pathways to elucidate cancer metabolic plasticity. Citation Format: Dongya Jia, Mingyang Lu, Kwang Hwa Jung, Jun Hyoung Park, José N. Onuchic, Benny Abraham Kaipparettu, Herbert Levine. Elucidating the metabolic plasticity of cancer by coupling gene regulation with metabolic pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2448.