A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth: The WarburQ effect

Abstract

Cancer cells share several metabolic traits, including aerobic production of lactate from glucose (Warburg effect), extensive glutamine utilization and impaired mitochondrial electron flow. It is still unclear how these metabolic rearrangements, which may involve different molecular events in different cells, contribute to a selective advantage for cancer cell proliferation. To ascertain which metabolic pathways are used to convert glucose and glutamine to balanced energy and biomass production, we performed systematic constraint-based simulations of a model of human central metabolism. Sampling of the feasible flux space allowed us to obtain a large number of randomly mutated cells simulated at different glutamine and glucose uptake rates. We observed that, in the limited subset of proliferating cells, most displayed fermentation of glucose to lactate in the presence of oxygen. At high utilization rates of glutamine, oxidative utilization of glucose was decreased, while the production of lactate from glutamine was enhanced. This emergent phenotype was observed only when the available carbon exceeded the amount that could be fully oxidized by the available oxygen. Under the latter conditions, standard Flux Balance Analysis indicated that: this metabolic pattern is optimal to maximize biomass and ATP production; it requires the activity of a branched TCA cycle, in which glutamine-dependent reductive carboxylation cooperates to the production of lipids and proteins; it is sustained by a variety of redox-controlled metabolic reactions. In a K-ras transformed cell line we experimentally assessed glutamine-induced metabolic changes. We validated computational results through an extension of Flux Balance Analysis that allows prediction of metabolite variations. Taken together these findings offer new understanding of the logic of the metabolic reprogramming that underlies cancer cell growth.

Integration of single-cell RNA-seq data into metabolic models to characterize tumour cell populations

“…As exchange of fatty acids between cells in tumours has been recently reported [2], we included the possibility to exchange palmitate via the TME and, accordingly, mitochondrial palmitate degradation and gluconeogenesis. Given the importance of reactive oxygen species (ROS) metabolism observed in [6], we also inserted ROS production and removal pathways. As the original version of the model does not include information on GPRs, such rules have been extracted from Recon 2.2 [36] and included in the HMRcore model, and recently manually curated [16]).…”

“…Metabolic rearranging, in particular, is a general feature of cancer cells, which reprogram their metabolism to feed their unrestrained proliferation, as it requires high amounts of energy and building-blocks [41]. The design principles underlying the causative role of metabolism in promoting growth as a function of the nutritional constraints are starting to be understood [6,35] and the idea of targeting the distinctive features of cancer metabolism has received considerable attention [40]. Unfortunately, recent evidences made clear that a single metabolic program cannot be used to globally define an altered tumour metabolism [3], as cancer cells, even within the same tumour, may cope with the above metabolic requirements by engaging different metabolic pathways [3].…”

Beyond Computational Genomics towards Systems Metabolomics for Precision Oncology

“…In this way we made the computational effort less demanding by not considering the large number of admissible wirings present in GWMM, which are not engaged in biomass production. A systematic constraintbased simulations of this core model (called ENGRO1) elucidated the interplay of glucose, glutamine and oxygen availability in setting the active wirings (47). At high utilization rates of glutamine, oxidative utilization of glucose is reduced, while the production of lactate from glutamine is increased.…”

“…2C). Reduction of glutamine availability reduces CMR and allows the utilization of glucose through standard TCA cycle, with lower production of biomass (47).…”

“…In the case of unrestricted cancer cell proliferation, the core function has been shown to be generated by a cancer metabolic rewiring (CMR). This fact allows to construct a constraint-based model, whose innovative investigation (47) has brought to the identification of design principles, yielding the rules which govern the basic property of cancer cells.…”