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.

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机械建模框架揭示了肿瘤代谢背后的关键原理

尽管有氧糖酵解或Warburg效应在很长时间以来一直被认为是肿瘤代谢的标志，但最近的研究揭示了更为复杂的情况。肿瘤细胞不仅在表现出Warburg效应时而且在其所依赖的营养物质和代谢途径中均表现出广泛的代谢异质性。而且，肿瘤细胞可以响应于环境线索和治疗干预而在不同的代谢表型之间切换。但是，缺乏分析观察到的代谢异质性和可塑性的框架。使用包括在肿瘤细胞中活跃的关键代谢途径的机制模型，我们表明细胞质中过量ATP对磷酸果糖激酶的抑制作用可驱动快速增殖的肿瘤细胞中有氧糖酵解的偏好。因此，就Warburg效应的表现而言，肿瘤细胞对ATP利用率的差异可能会导致异质性。基于此思想，我们将肿瘤细胞的代谢表型与其迁移表型耦合，并表明我们的模型预测与先前的实验相符。接下来，我们报告说，增殖细胞对不同的动脉粥样硬化途径的依赖性取决于葡萄糖和谷氨酰胺的相对可用性，并且可以进一步推动代谢异质性。最后，以使用BRAF抑制剂的黑色素瘤细胞治疗为例，我们表明我们的模型可用于预测响应药物治疗的癌细胞的代谢和基因表达变化。与以前的肿瘤代谢建模方法相比，通过做出更具普遍性和可解释性的预测，我们的框架确定了控制肿瘤细胞代谢的关键原理以及所报道的异质性和可塑性。这些原则可能是针对癌症的代谢脆弱性的关键。