Epithelial-to-mesenchymal transition (EMT) has been associated with cancer cell heterogeneity, plasticity, and metastasis. However, the extrinsic signals supervising these phenotypic transitions remain elusive. To assess how selected microenvironmental signals control cancer-associated phenotypes along the EMT continuum, we defined a logical model of the EMT cellular network that yields qualitative degrees of cell adhesions by adherens junctions and focal adhesions, two features affected during EMT. The model attractors recovered epithelial, mesenchymal, and hybrid phenotypes. Simulations showed that hybrid phenotypes may arise through independent molecular paths involving stringent extrinsic signals. Of particular interest, model predictions and their experimental validations indicated that: (i) stiffening of the extracellular matrix was a prerequisite for cells overactivating FAK\_SRC to upregulate SNAIL and acquire a mesenchymal phenotype and (ii) FAK\_SRC inhibition of cell–cell contacts through the receptor-type tyrosine-protein phosphatases kappa led to acquisition of a full mesenchymal, rather than a hybrid, phenotype. Altogether, these computational and experimental approaches allow assessment of critical microenvironmental signals controlling hybrid EMT phenotypes and indicate that EMT involves multiple molecular programs. Significance: A multidisciplinary study sheds light on microenvironmental signals controlling cancer cell plasticity along EMT and suggests that hybrid and mesenchymal phenotypes arise through independent molecular paths.

中文翻译：

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混合上皮-间充质表型受微环境因素控制。

上皮到间质转化（EMT）与癌细胞异质性，可塑性和转移有关。然而，监督这些表型转变的外部信号仍然难以捉摸。为了评估选定的微环境信号如何沿EMT连续体控制癌症相关的表型，我们定义了EMT细胞网络的逻辑模型，该模型通过粘附连接和局部粘附产生定性程度的细胞粘附，这是在EMT过程中受到影响的两个特征。模型吸引子恢复上皮，间质和杂种表型。模拟表明，杂合表型可能通过涉及严格的外在信号的独立分子途径产生。特别令人感兴趣的是，模型预测及其实验验证表明：（i）细胞外基质的硬化是细胞过度激活FAK \ _SRC以上调SNAIL和获得间质表型的先决条件；（ii）FAK \ _SRC通过受体型酪氨酸-蛋白磷酸酶kappa导致的细胞间接触抑制获得完整的间充质而非混合表型。总之，这些计算和实验方法可以评估控制混合EMT表型的关键微环境信号，并表明EMT涉及多个分子程序。启示：一项多学科研究揭示了沿EMT控制癌细胞可塑性的微环境信号，并表明杂交和间充质表型是通过独立的分子途径产生的。