葡萄糖剥夺癌细胞的进化动力学：来自实验启发数学建模的洞见
Evolutionary dynamics of glucose-deprived cancer cells: insights from experimentally-informed mathematical modelling
AI总结：
该研究结合乳腺癌体外实验与结构化偏积分微分方程模型，揭示乳酸信号诱导和表观遗传波动如何通过MCT1表达变化驱动癌细胞适应葡萄糖剥夺。
摘要：
葡萄糖是癌细胞的主要能量来源。多条证据支持以下观点：单羧酸转运蛋白（如MCT1）会在葡萄糖匮乏环境中引发癌细胞的代谢重编程，使其能够将葡萄糖代谢副产物乳酸重新用作替代能源，并对疾病进展产生严重后果。我们采用实验与数学建模协同的方法，探究癌细胞适应葡萄糖剥夺背后的进化过程，尤其关注在葡萄糖剥夺的侵袭性癌细胞中观察到的MCT1表达升高机制。基于乳腺癌细胞体外实验获得的数据被用于启发并校准一个数学模型，该模型包含一个偏积分微分方程，用以描述按MCT1表达水平结构化的癌细胞种群动力学。模型的解析与数值结果表明，由乳酸相关信号通路介导、受环境诱导的MCT1表达变化，可使葡萄糖剥夺的癌细胞产生快速适应性反应；同时，表观遗传变化导致的MCT1表达波动为环境选择提供了作用底物，加速了癌细胞适应葡萄糖剥夺所依赖的选择性清扫，并可能构成一种长期的风险对冲机制。
英文摘要：
Glucose is a primary energy source for cancer cells. Several lines of evidence support the idea that monocarboxylate transporters, such as MCT1, elicit metabolic reprogramming of cancer cells in glucose-poor environments, allowing them to reuse lactate, a byproduct of glucose metabolism, as an alternative energy source with serious consequences for disease progression. We employ a synergistic experimental and mathematical modelling approach to explore the evolutionary processes at the root of cancer cell adaptation to glucose deprivation, with particular focus on the mechanisms underlying the increase in MCT1 expression observed in glucose-deprived aggressive cancer cells. Data from in vitro experiments on breast cancer cells are used to inform and calibrate a mathematical model that comprises a partial integro-differential equation for the dynamics of a population of cancer cells structured by the level of MCT1 expression. Analytical and numerical results of this model suggest that environment-induced changes in MCT1 expression mediated by lactate-associated signalling pathways enable a prompt adaptive response of glucose-deprived cancer cells, whilst fluctuations in MCT1 expression due to epigenetic changes create the substrate for environmental selection to act upon, speeding up the selective sweep underlying cancer cell adaptation to glucose deprivation, and may constitute a long-term bet-hedging mechanism.
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