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 TCGA patient transcriptomics data of multiple cancer types and single-cell RNA-seq data of lung adenocarcinoma, we confirmed an anti-correlation 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.

Drug-tolerant idling melanoma cells exhibit theory-predicted metabolic low-low phenotype

“…Here, we report that the SKMEL5 melanoma cells can indeed repress both their glycolysis and OXPHOS activity when they transition into the idling state as a response to therapy. Furthermore, using the RNA-sequencing (RNA-Seq) data of human melanoma M397 and M229 cell lines and melanoma patient samples from from Gene Expression Omnibus (GEO), we show that melanoma cells consistently decrease their glycolysis and/or OXPHOS activity and exhibit a convergence toward the L/L phenotype upon long-term MAPKi treatment, as characterized by the AMPK/HIF-1 signatures (15) and the metabolic pathway scores (3). The residual melanoma tumors may be composed of a significant fraction of drug-tolerant idling cells.…”

FRK plays an oncogenic role in non‐small cell lung cancer by enhancing the stemness phenotype via induction of metabolic reprogramming

“…The important characteristics of metabolic reprogramming include the Warburg effect (accelerated glucose transport, aerobic glycolysis and lactate production) and abnormal fatty acid biogenesis, whereas mitochondrial oxidative phosphorylation and high mitochondrial activity are also essential for rapid tumor cell proliferation . Moreover, oxidative phosphorylation plays a crucial role in tumor progression by promoting the hybrid state of cancer cells, which adapts the cancer cells to various microenvironments . Src activation elevates aerobic glycolysis by inducing phosphorylation of lactate dehydrogenase A while Src kinase inhibition leads to a decrease in mitochondrial respiration via a specific decrease in complex I activities (nicotinamide adenine dinucleotide–ubiquinone oxidoreductase) .…”

“…16 Moreover, oxidative phosphorylation plays a crucial role in tumor progression by promoting the hybrid state of cancer cells, which adapts the cancer cells to various microenvironments. 17 Src activation elevates aerobic glycolysis by inducing phosphorylation of lactate dehydrogenase A while Src kinase inhibition leads to a decrease in mitochondrial respiration via a specific decrease in complex I activities (nicotinamide adenine dinucleotideubiquinone oxidoreductase). 18 However, the mechanism underlying the role of the Src family in metabolic reprogramming regulation remains unclear.…”

Fluorinated Boron Nitride Quantum Dots: A New 0D Material for Energy Conversion and Detection of Cellular Metabolism

“…Considering this possibility, for our study we choose benign human mammary epithelial cell lines (HMLE) and highly metastatic breast cancer cells (MDA‐MB‐231 cells) to understand the role of pH variation in the quenching of fluorescence in a biological setting. Even though MDA‐MB‐231 cells have high energy dependency on mitochondrial fatty acid oxidation pathway, these aggressive cancer cells also maintain a hybrid metabolic status with increased glycolytic and oxidative phosphorylation (OXPHOS) status . The details of cell culture and the drug treatment are given in Section S4 in the Supporting Information.…”

“…Even though MDA-MB-231 cells have high energy dependency on mitochondrial fatty acid oxidation pathway, [53] these aggressive cancer cells also maintain a hybrid metabolic status with increased glycolytic and oxidative phosphorylation (OXPHOS) status. [54] The details of cell culture and the drug treatment are given in Section S4 in the Supporting Information.…”