Selvaggio2020 - Microenvironment control of hybrid Epithelial-Mesenchymal phenotypes

Epithelial to Mesenchymal Transition (EMT) has been associated with cancer cell heterogeneity, plasticity and metastasis. It has been the subject of several modeling effort. This logical model of the EMT cellular network aims to assess microenvironmental signals controlling cancer-associated phenotypes amid the EMT continuum. Its outcomes relate to the qualitative degrees of cell adhesions by adherent junctions and focal adhesions, two features affected during EMT. Model attractors recover epithelial, mesenchymal and hybrid phenotypes, and simulations show that hybrid phenotypes may arise through independent molecular paths, involving stringent extrinsic signals.
Of particular interest, model predictions and their experimental validations indicated that: 1) ECM stiffening is a prerequisite for cells overactivating FAK-SRC to upregulate SNAIL1 and acquire a mesenchymal phenotype, and 2) FAK-SRC inhibition of cell-cell contacts through the Receptor Protein Tyrosine Phosphates kappa leads to the acquisition of a full mesenchymal rather than a hybrid phenotype.

上皮间质转化（Epithelial to Mesenchymal Transition, EMT）已被证实与癌细胞异质性、可塑性及转移密切相关，该过程已成为多项建模研究的核心关注主题。本EMT细胞网络逻辑模型旨在解析上皮间质转化连续体中调控癌症相关表型的微环境信号。其输出结果与黏着连接和黏着斑介导的细胞黏附的定性程度相关——这两类细胞黏附结构均在EMT进程中发生显著改变。模型吸引子可复现上皮表型、间质表型及杂合表型；仿真实验结果表明，杂合表型可通过多条独立分子通路产生，且依赖于严格的外源性信号调控。
尤为值得关注的是，模型预测及其实验验证结果显示：1）细胞外基质（Extracellular Matrix, ECM）硬化是细胞过度激活黏着斑激酶-肉瘤激酶（FAK-SRC）以上调SNAIL1基因表达并获得间质表型的必要前提；2）FAK-SRC通过受体蛋白酪氨酸磷酸酶κ（Receptor Protein Tyrosine Phosphates kappa）抑制细胞间连接，可促使细胞完全转化为间质表型而非杂合表型。