Background: The Warburg effect, historically regarded as a hallmark of cancer metabolism, is often interpreted as a universal metabolic feature of tumor cells. However, accumulating experimental evidence challenges this paradigm, revealing a more nuanced and context-dependent metabolic landscape.Methods: In this study, we present a hybrid multiscale model of tumor metabolism that integrates cellular and environmental dynamics to explore the emergence of metabolic phenotypes under varying conditions of stress. Our model combines a reduced yet mechanistically informed description of intracellular metabolism with an agent-based framework that captures spatial and temporal heterogeneity across tumor tissue. Each cell is represented as an autonomous agent whose behavior is shaped by local concentrations of key diffusive species—oxygen, glucose, lactate, and protons—and governed by internal metabolic states, gene expression levels, and environmental feedback. Building on our previous work, we extend existing metabolic models to include the reversible transport of lactate and the regulatory role of acidity in glycolytic flux.Results: Simulations under different environmental perturbations—such as oxygen oscillations, acidic shocks, and glucose deprivation—demonstrate that the Warburg effect is neither universal nor static. Instead, metabolic phenotypes emerge dynamically from the interplay between a cell’s history and its local microenvironment, without requiring genetic alterations.Conclusions: Our findings suggest that tumor metabolic behavior is better understood as a continuum of adaptive states shaped by thermodynamic and enzymatic constraints. This systems-level perspective offers new insights into metabolic plasticity and may inform therapeutic strategies targeting the tumor microenvironment rather than intrinsic cellular properties alone.
背景：瓦伯格效应历来被视为癌症代谢的标志，常被解读为肿瘤细胞的普遍代谢特征。然而，越来越多的实验证据对这一范式提出挑战，揭示出更为复杂且具有情境依赖性的代谢图景。 方法：本研究提出一种肿瘤代谢的混合多尺度模型，该模型整合了细胞与环境动态，以探索不同应激条件下代谢表型的形成。模型结合了机制性简化的细胞内代谢描述与基于智能体的框架，后者能够捕捉肿瘤组织在空间和时间上的异质性。每个细胞被表征为自主智能体，其行为受局部关键扩散物质（氧气、葡萄糖、乳酸和质子）浓度的影响，并由内部代谢状态、基因表达水平和环境反馈共同调控。基于我们先前的研究，我们扩展了现有代谢模型，纳入乳酸的可逆转运以及酸度在糖酵解通量中的调节作用。 结果：在不同环境扰动（如氧气波动、酸性冲击和葡萄糖剥夺）下的模拟表明，瓦伯格效应既非普遍存在也非静态不变。相反，代谢表型动态地产生于细胞历史与其局部微环境之间的相互作用，无需基因改变。 结论：我们的研究结果表明，肿瘤代谢行为更宜理解为受热力学和酶学约束塑造的适应性状态连续体。这一系统层面的视角为代谢可塑性提供了新的见解，并可能为针对肿瘤微环境而非仅针对细胞内在特性的治疗策略提供参考。
Beyond the Warburg Effect: Modeling the Dynamic and Context-Dependent Nature of Tumor Metabolism
肿瘤(癌症)患者之家