A mechanistic modeling framework reveals the key principles underlying tumor metabolism

Abstract

While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the nutrients and the metabolic pathways they are dependent on. Moreover, tumor cells can switch between different metabolic phenotypes in response to environmental cues and therapeutic interventions. A framework to analyze the observed metabolic heterogeneity and plasticity is, however, lacking. Using a mechanistic model that includes the key metabolic pathways active in tumor cells, we show that the inhibition of phosphofructokinase by excess ATP in the cytoplasm can drive a preference for aerobic glycolysis in fast-proliferating tumor cells. The differing rates of ATP utilization by tumor cells can therefore drive heterogeneity with respect to the presentation of the Warburg effect. Building upon this idea, we couple the metabolic phenotype of tumor cells to their migratory phenotype, and show that our model predictions are in agreement with previous experiments. Next, we report that the reliance of proliferating cells on different anaplerotic pathways depends on the relative availability of glucose and glutamine, and can further drive metabolic heterogeneity. Finally, using treatment of melanoma cells with a BRAF inhibitor as an example, we show that our model can be used to predict the metabolic and gene expression changes in cancer cells in response to drug treatment. By making predictions that are far more generalizable and interpretable as compared to previous tumor metabolism modeling approaches, our framework identifies key principles that govern tumor cell metabolism, and the reported heterogeneity and plasticity. These principles could be key to targeting the metabolic vulnerabilities of cancer.

Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer

“…The coupling of the E/M and W/O states is somewhat surprising given the widespread impression that primary tumors often exhibit the Warburg effect, possibly because of their need to limit the amount of ATP produced in favor of maximizing biomass production and growth (see 40 and references therein). However, this finding is consistent with the general idea that moving from E to E/M correlates with increasing stemness, and stem-like capabilities often rely on glycolysis.…”

Inhibition of Lactate Dehydrogenase Reduces the Survival of Metastatically Active Lewis Lung Carcinoma Cells

“…This discovered fact -the presence of resistant cells to LDH blockade -answers the question to some extent, why attempts to use LDH inhibition to treat cancer have not progressed beyond early stage clinical trials. Tumors are metabolically flexible [11], which may explain why loss of LDH activity does not affect their progression in vivo. When LDH is blocked, tumors are unable to use glucose to produce lactate, but they can take up other metabolites, such as glutamine, to produce and increase the metabolites needed during proliferation.…”

Development of long-term primary cell culture of Macrobrachium rosenbergii: morphology, metabolic activity, and cell-cycle analysis

“…Cells can switch between different metabolic pathways based on their microenvironment and needs. Cancer cells at certain periods used aerobic glycolysis to convert glucose into energy (Tripathi et al, 2022). Based on the drop-in metabolic activity of cells in culture, such a process might occur on days 4, 8, 12, and 26 in the prawn embryonic primary cell culture.…”