title: Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation.
abstract: Abnormal metabolism is a hallmark of cancer, yet its regulation remains poorly understood. Cancer cells were considered to utilize primarily glycolysis for ATP production, referred to as the Warburg effect. However, recent evidence suggests that oxidative phosphorylation (OXPHOS) plays a crucial role during cancer progression. Here we utilized a systems biology approach to decipher the regulatory principle of glycolysis and OXPHOS. 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 a hybrid state with both metabolic modes coexisting. This was due to higher ROS production and/or oncogene activation, such as RAS, MYC, and c-SRC. Guided by the model, we developed two signatures consisting of AMPK and HIF-1 downstream genes, respectively, to quantify the activity of glycolysis and OXPHOS. By applying the AMPK and HIF-1 signatures to The Cancer Genome Atlas patient transcriptomics data of multiple cancer types and single-cell RNA-seq data of lung adenocarcinoma, we confirmed an anticorrelation between AMPK and HIF-1 activities and the association of metabolic states with oncogenes. We propose that the hybrid phenotype contributes to metabolic plasticity, allowing cancer cells to adapt to various microenvironments. Using model simulations, our theoretical framework of metabolism can serve as a platform to decode cancer metabolic plasticity and design cancer therapies targeting metabolism.Cancer Res; 77(7); 1564-74. ©2017 AACR.
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas.|Applied Physics Program, Rice University, Houston, Texas.
authors.forename: Linglin
authors.initials: L
authors.lastname: Yu
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas. jonuchic@rice.edu kaippare@bcm.edu mingyang.lu@jax.org.|The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Lu
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas.|Systems, Synthetic and Physical Biology Program, Rice University, Houston, Texas.
authors.forename: Dongya
authors.initials: D
authors.lastname: Jia
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas.|Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas.|Department of Bioengineering, Rice University, Houston, Texas.
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Ma
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas.|School of Physics and Astronomy, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Eshel
authors.initials: E
authors.lastname: Ben-Jacob
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas.|Department of Bioengineering, Rice University, Houston, Texas.|Department of Biosciences, Rice University, Houston, Texas.|Department of Physics and Astronomy, Rice University, Houston, Texas.
authors.forename: Herbert
authors.initials: H
authors.lastname: Levine
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. jonuchic@rice.edu kaippare@bcm.edu mingyang.lu@jax.org.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Benny Abraham
authors.initials: BA
authors.lastname: Kaipparettu
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas. jonuchic@rice.edu kaippare@bcm.edu mingyang.lu@jax.org.|Department of Biosciences, Rice University, Houston, Texas.|Department of Physics and Astronomy, Rice University, Houston, Texas.|Department of Chemistry, Rice University, Houston, Texas.
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D006019:Glycolysis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D010085:Oxidative Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D051793:Hypoxia-Inducible Factor 1; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D055372:AMP-Activated Protein Kinases