Abstract
Abstract Abnormal metabolism is a hallmark of cancer, yet its regulatory mechanism is poorly understood. Cancer cells were considered to mostly utilize glycolysis, referred to as the Warburg effect. However recent evidence suggests that oxidative phosphorylation also plays a crucial role during cancer progression. Here we utilized a systems biology approach to decipher the regulatory principle of glycolysis and oxidative phosphorylation. Integrating information from literature, we constructed a regulatory network of genes and metabolites, from which we extracted a core circuit containing HIF-1, AMPK and ROS. Our circuit analysis showed that while normal cells have an oxidative state and a glycolytic state, cancer cells can access an additional hybrid state with both metabolic modes coexisting, due to higher ROS production and/or oncogenic activation, such as RAS, MYC and c-SRC. The anti-correlation between AMPK and HIF-1 and the association of metabolic states with oncogenes were further confirmed using TCGA patient transcriptomics data of multiple cancer types and single-cell RNA-seq data of lung adenocarcinoma. We propose that the hybrid phenotype contributes to metabolic plasticity, allowing cancer cells to adapt to various microenvironments. Using model simulations, we predicted the efficacies of several metabolic cancer therapies based on their effectiveness in reducing metabolic plasticity. Our theoretical framework of metabolism can serve as a platform to decode cancer metabolic plasticity and design cancer therapies targeting metabolism. Citation Format: Dongya Jia, Linglin Yu, Mingyang Lu, Eshel Ben-Jacob, Jianpeng Ma, Herbert Levine, Benny A. Kaipparettu, Jose Onuchic. Towards decoding the interplay between glycolysis and oxidative phosphorylation in 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 5568. doi:10.1158/1538-7445.AM2017-5568
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