Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways

Abstract

Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities. Previously, by modeling the gene regulation of cancer metabolism we have reported that cancer cells can acquire a stable hybrid metabolic state in which both glycolysis and OXPHOS can be used. Here, to comprehensively characterize cancer metabolic activity, we establish a theoretical framework by coupling gene regulation with 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 major metabolic pathways: glucose oxidation, glycolysis, and fatty acid oxidation. Our model further characterizes the hybrid metabolic state and a metabolically inactive state where cells have low activity of both glycolysis and OXPHOS. We verify the model prediction using metabolomics and transcriptomics data from paired tumor and adjacent benign tissue samples from a cohort of breast cancer patients and RNA-sequencing data from The Cancer Genome Atlas. We further validate the model prediction by in vitro studies of aggressive triple-negative breast cancer (TNBC) cells. The experimental results confirm that TNBC cells can maintain a hybrid metabolic phenotype and targeting both glycolysis and OXPHOS is necessary to eliminate their metabolic plasticity. In summary, our work serves as a platform to symmetrically study how tuning gene activity modulates metabolic pathway activity, and vice versa.

Disruption of Redox Balance Enhances the Effects of BRAF-inhibition in Melanoma Cells

“…Further studies are required to ascertain the species of ROS that have detrimental effects on melanoma cells. One could imagine this could be cell-line or tumor specific, as gene regulatory network (GRN) has been linked with the ability of cells to undergo metabolic plasticity (Jia et al, 2019;Paudel and Quaranta, 2019) . Future work seems necessary to also investigate the compensatory antioxidant pathways, and how they help maintain redox homeostasis in melanoma cells (Harris et al, 2015) .…”

“…Recent studies have shown that cancer cells can utilize glycolysis, mitochondrial respiration, or both, depending on their environment (Dang, 2012) . Furthermore, cancer cells can adapt metabolically in response to external perturbations (DeBerardinis et al, 2008;Jia et al, 2019) . This metabolic flexibility provides cancer cells with energy, and necessary intermediates for biosynthetic processes required for survival and to maintain redox balance under changing environments (DeBerardinis et al, 2008;Paudel and Quaranta, 2019) .…”

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.…”

“…To elucidate metabolic plasticity in cancer, we established a modeling framework that couples gene regulation with metabolic pathways (Supplementary Fig. S1) (3). Our modeling analysis demonstrates a direct association of the master gene regulators of cancer metabolism AMPactivated protein kinase (AMPK) and hypoxia-inducible factor (HIF)-1 with three major metabolic pathways -glycolysis, glucose oxidation and fatty acid oxidation (FAO).…”

Recent advances in metabolomics of triple negative breast cancer

“…In another study, [U‐13C]‐glucose or [U‐13C]‐glutamine by NMR analysis recognized differentiation mechanisms of that Luminal A and triple‐negative. breast cancer with differential expression of hormonal receptors exhibited different utilization of energy . O'day (2018) performed unbiased nuclear magnetic resonance spectroscopy screening to identify altered bioenergetics in metastatic cancer.…”