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Title: 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}
Article:
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.
Introduction:
Cancer is a network disease[1] resulting from a variable combination of genetic and epigenetic alterations and selection of selfish cells, which maximize their fitness at the expense of the organism[2]. Despite the high morphological, genetic and molecular heterogeneity[3], cancer cells share a restricted number of essential alterations in cell physiology, better known as hallmarks[4]. A reorganization of the hallmarks[5] identifies in the enhanced, unrestricted cell growth the basic property of cancer cells. This property requires an extensive reorganization of metabolic fluxes[6–9], characterized by an enhancement in aerobic glycolysis—the well-known Warburg effect[10]—and by the utilization of glutamine as a source of both carbon and nitrogen to support cellular biosyntheses. While the involvement of glucose in cancer cell metabolism has been widely studied, its integration with the utilization of glutamine through a reductive carboxylation pathway[11–18] leaves many aspects unresolved, given that the two pathways appear to be decoupled[19], but somehow coordinated[20]. These perturbations in key metabolic pathways not only propel cells towards malignancy, but also drive changes in the tissue microenvironment–ultimately helping cells to break through the physical constraints of their surrounding stroma and to evade immune recognition[21]. A deeper understanding on how cancer metabolic rewiring( CMR) drives initiation, maintenance and progression of the disease would thus be of considerable interest. In order to integrate sets of experimental data and to formulate new testable hypotheses, complex biological systems–such as human metabolism that involves thousands of metabolites and reactions—need to be formally described by mathematical models. In this regard, constraint-based modeling and in particular Flux Balance Analysis( FBA), which is based on the definition and manipulation of stoichiometric matrices and was originally developed for the optimization of microbial strains, is rapidly gaining popularity within life sciences[22]. FBA allows to identify a phenotype that maximizes a certain objective( typically growth) among all the possible flux patterns compatible with the steady state assumption. In biological terms, these flux patterns may result from the expression and catalytic competence of the corresponding enzymes according to substrate availability, or, to use our terminology, from different wirings. FBA may be applied to genome-wide metabolic networks[23, 24], which include the stoichiometry of the vast majority of chemical reactions that are catalyzed by enzymes encoded by the human genome. These maps have been effectively exploited as a scaffold for ‘omic’ data integration, proving able to identify essential genes and reporter metabolites in metabolic disorders and cancer[24–26]. In data-driven FBA studies of cancer metabolism[27, 28], aerobic glycolysis has been typically imposed on the network. However, if we want to derive the design principles that control metabolic rewiring in cancer cells and link them to enhanced proliferation, we need to let CMR emerge from the simulated boundary conditions. Being highly detailed, genome-wide models require many assumptions on in-vivo nutrient utilization rates. Moreover, when the aim is to investigate the plethora of admissible wirings, rather than to determine optimality, their computation becomes demanding and may give origin to a combinatorial explosion of different flux patterns, which fuels mere details while masking the major regulatory connections. Manually curated core models including hundreds of metabolites, selected for the specific purpose of the analysis, help to overcome the problems above[29, 30]. We therefore expect them to increase the knowledge on the system and generate novel, experimentally testable predictions. In this study, we aim to identify the regulatory principles that link the utilization of glucose and glutamine in originating the Warburg effect, and ultimately in driving cancer cell growth. We manually reconstructed a core stoichiometric model designed to evaluate the contribution of glucose and glutamine to enhanced growth, hence the name ENGRO1( ENhanced GROwth). By exploring the space of admissible wirings of the ENGRO1 model, we newly identified and rationalized intense aerobic glycolysis and glutamine reductive carboxylation as the fittest emergent strategy that supports cancer cell growth under conditions reported to be generated by oncogenic activation: sustained glucose and glutamine uptake. This emergent phenotype is observed only when the available carbon exceeds the amount that could be fully oxidized by the available oxygen, a condition that is entirely physiological. We validated our predictions by analyzing the metabolic behavior of murine K-ras transformed fibroblasts, grown in high glucose together with either low or high glutamine availability.
Discussion:
In this work, we exploited a novel constraint-based approach, based on the systematic evaluation of the possible wirings of the metabolic network required for the formation of biomass from glucose and glutamine, under different nutritional conditions. The first discovery presented in this paper is the identification of boundary conditions that taken together promote the emergence of cancer metabolic rewiring. In the presence of an increased uptake of glucose and glutamine, the availability of intracellular oxygen is not sufficient to fully oxidize all carbon provided by both glucose and glutamine. This oxidative bottleneck is not given by the actual oxygen concentration per se, but rather by the ratio between the ability to consume oxygen and the available nutrients, i. e., glucose and glutamine. A condition in which there are less than 6 usable O2 molecules per glucose molecule may be typical for cancer cells. Detailed calculations—based on oxygen consumption rates reported in[59] and glucose consumption rates reported in[60] and in Fig 3—are extended in Materials and Methods. They indicate that even under the atmospheric conditions of our cell cultures, the oxygen consumption is not 6 times as much as that of glucose, therefore fitting within the boundary conditions described above. Also in vivo the oxygen to glucose ratio in the blood supply is at least 3 times less than the 6 required for complete respiration( see Materials and methods). The elevated glutamine consumption rates of cancer cells make this oxidative bottleneck even more effective. The oxygen concentration in peripheral tissues might be even much lower as conditions change dynamically between the periphery and the center of a tumor[61], as well as during its natural history. For instance, most solid tumors face a period of actual poor oxygen availability before neo-angiogenesis begins. During this period cells better able to cope with low oxygen conditions—or carrying mutations leading to a mitochondrial dysfunction limiting the ability of Complex I to accept electrons from NADH[62, 63] that would mimic actual oxygen limitation–are likely to be selected for. These cells would internalize more glucose than what can be fully oxidized. Indeed, various oncogenes have been reported to cause stimulated uptake of nutrients. In general, the rewiring here described should become advantageous for highly proliferating cells, such as cancer cells. Its associated possible drawbacks, such as the excretion of potentially toxic lactate and ammonia, would make it less favorable for normal, slowly proliferating or resting cells. We have quantitatively shown that high glucose uptake rates have the side benefit of making growth rates less sensitive to oxygen variations. As most cancer cells result from mutation and selection, tumors might therefore have fixed, through mutations, advantageous phenotypes into their genotype. In such a situation with high mutation rates, the population will tend to lose( through mutations and thereby permanently) all activities it does not depend upon. Following the agreement with a wealth of literature, as well as experimental validation, of main ENGRO1 model predictions, we analyzed the global in silico flux distribution that sustains CMR. We were able to integrate and rationalize the role of the various pathways observed in independent studies on cancer metabolism, as follows: By exploiting FBA, we investigated the relationship between different flux modes and their associated growth capability. We discovered that CMR is characterized by the following novel design principles: Aerobic production of lactate from glucose does not utilize all chemical potential of its substrate, thus it is generally regarded as unfit. Our results indicate that this is not the case. The phenomenon we observed in silico at limiting oxygen is not simply the fermentation of spare glucose, but a competition for oxygen between glutamine and glucose. The limiting amount of oxygen is preferentially used for the oxidation of the NADH and FADH2 generated when glutamine is converted to building blocks and lactate. As all available glucose is converted to lactate, we put forward a novel interpretation to what is classically understood as the ‘Warburg effect’. As boundary conditions change, so do the flux distributions of virtual cells that allow–possibly sub-optimal—biomass accumulation under a variety of conditions, suggesting how cancer cells might be able to follow different metabolic routes in vivo, if the tumor environment imposes different constraints. In particular, we showed that fermentation of glutamine to lactate( that we call WarburgQ effect) is able to sustain growth even when glutamine is the exclusive simulated carbon source, suggesting how WarburgQ cells would be able to evade therapies that target only glycolysis. In conclusion, our paper offers for the first time a “logic” to the central role of the metabolic hallmarks in cancer biology, logic that was envisioned in[4]. As the generalizability of predictions of metabolomics through FBA methods needs further research, it should be useful to engage in stable isotope-labeling studies and detailed mathematical analyses of the results to confirm our findings further. In the next-future, the general traits of cancer metabolic rewiring identified with our approach will be better detailed by means of more fine-grained models, taking into account compartmentalization and the role of metabolic shuttles, hence opening the way to more efficient approaches to drug discovery and to precision medicine not only for cancer, but also for other diseases in which a remodeling of metabolism has a relevant role, such as metabolic syndrome, ageing and neurodegeration.
Hallmarks describing common key events in initiation , maintenance and progression of cancer have been identified . One hallmark deals with rewiring of metabolic reactions required to sustain enhanced cell proliferation . The availability of molecular , mechanistic models of cancer hallmarks will mightily improve optimized personal treatment and new drug discovery . Metabolism is the only hallmark for which it is currently possible to derive large scale mathematical models , which have predictive ability . In this paper , we exploit a constraint-based model of the core metabolism required for biomass conversion of the most relevant nutrients—glucose and glutamine—to clarify the logic of control of cancer metabolism . We newly report that , when available oxygen is not sufficient to fully oxidize available glucose and glutamine carbons–a situation compatible with that observed under normal oxygen conditions in human and in cancer cells growing in vitro—utilization of glutamine by reductive carboxylation and conversion of glucose and glutamine to lactate confer advantage for biomass production . Redox homeostasis can be maintained through the use of different alternative pathways . In conclusion , this paper offers a logic interpretation to the link between metabolic rewiring and enhanced proliferation , which may offer new approaches to targeted drug discovery and utilization .