乳腺癌EMT过程的动力学建模与分岔分析

Dynamical Modeling and Bifurcation Analysis of the Epithelial-Mesenchymal Transition Process in Breast Cancer

摘要: 乳腺癌是全球女性最常见的恶性肿瘤之一，其高死亡率主要源于肿瘤转移。上皮–间质转化(EMT)是驱动转移的关键步骤，其核心调控网络涉及miR-200、ZEB1和CDH1之间的复杂相互作用。本研究通过构建该网络的三维动力学模型并运用分岔理论，深入揭示了EMT的动态调控机制。分析表明，ZEB1对miR-200和CDH1的抑制强度可作为关键开关，通过诱导鞍结分岔直接影响细胞状态的稳定性。进一步的双参数分析揭示了更复杂的调控景观，ZEB1与miR-200的相互抑制强度、以及ZEB1对miR-200的抑制与CDH1对ZEB1的抑制这两组参数组合，均能引发导致表型突变的尖点分岔。这些研究结果表明，精准调控关键参数可有效维持上皮状态或抑制EMT进程，从而为逆转乳腺癌转移提供了重要的理论依据。

Abstract: Breast cancer is one of the most common malignant tumors in women worldwide, and its high mortality rate mainly stems from tumor metastasis. The epithelial-mesenchymal transition (EMT) is a key step driving metastasis, and its core regulatory network involves the complex interactions among miR-200, ZEB1, and CDH1. This study, by constructing a three-dimensional dynamic model of this network and applying bifurcation theory, deeply reveals the dynamic regulatory mechanism of EMT. Analysis indicates that the inhibition strengths of ZEB1 on miR-200 and CDH1 can act as critical switches, directly affecting the stability of cellular states by inducing saddle-node bifurcations. Further two-parameter analysis revealed a more complex regulatory landscape: the mutual inhibition strength between ZEB1 and miR-200, as well as the combination of ZEB1’s inhibition on miR-200 and CDH1’s inhibition on ZEB1, can both trigger cusp bifurcations that lead to phenotypic mutations. These research results indicate that precise regulation of the key parameters can effectively maintain the epithelial state or inhibit the EMT process, thereby providing an important theoretical basis for reversing breast cancer metastasis.