Pathak Amit
Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, Missouri.
Biophys J. 2016 Oct 4;111(7):1496-1506. doi: 10.1016/j.bpj.2016.08.034.
Epithelial-to-mesenchymal transition (EMT) enables scattering of cell clusters and disseminates motile cells to distant locations in vivo during embryonic development and cancer metastasis. Both stiffness and topography of the extracellular matrix (ECM) have been shown to influence EMT. In this work, we examine how the integrity of epithelial cell clusters is regulated by subcellular forces, protrusions, and adhesions for varying ECM inputs, such as stiffness, topography, and dimensionality. Our model simulates multicell networks of defined sizes and shapes in ECMs of varied stiffness and geometry. The integrity of cell clusters is dictated by cell-cell junctions, which depend on subcellular forces and adhesion dynamics within each cell of the cluster. Our simulations demonstrate an enhanced dissociation of cell-cell junctions in stiffer and more confined three-dimensional (3D) environments, consistent with experimental findings. In narrow channels, the cell edges parallel to the axis of channels lose their cell-cell junctions more readily than those oriented in the perpendicular direction. The inhibition of protrusive activity and cell polarity disables confinement-dependent cell scattering. Here, cell adhesion and spreading along channel walls is found to be essential for scattering. The model also predicts that two-dimensional (2D) confinement of clusters restricts cell spreading and simultaneously blunts the confinement-sensitive cell scattering. This new, to our knowledge, multiscale model integrates molecular adhesion dynamics, subcellular forces, cellular deformation, and macroscale mechanical properties of the ECM to predict the state of cell clusters of defined shapes and sizes. The predictions made by our model not only match experimental findings from a number of experimental setups, but also provide a new conceptual framework for understanding mechanosensitive cell scattering and EMT.
上皮-间质转化（EMT）能使细胞簇分散，并在胚胎发育和癌症转移过程中将运动性细胞播散到体内远处。细胞外基质（ECM）的硬度和拓扑结构均已显示会影响EMT。在这项工作中，我们研究了对于不同的ECM输入（如硬度、拓扑结构和维度），上皮细胞簇的完整性是如何由亚细胞力、突起和黏附所调控的。我们的模型模拟了在具有不同硬度和几何形状的ECM中确定大小和形状的多细胞网络。细胞簇的完整性由细胞间连接决定，而细胞间连接取决于簇内每个细胞的亚细胞力和黏附动力学。我们的模拟表明，在更硬且更受限的三维（3D）环境中，细胞间连接的解离增强，这与实验结果一致。在狭窄通道中，平行于通道轴的细胞边缘比垂直方向的细胞边缘更容易失去细胞间连接。对突出活动和细胞极性的抑制会使依赖于限制的细胞散射失效。在此，发现细胞沿通道壁的黏附和铺展对于散射至关重要。该模型还预测，簇的二维（2D）限制会限制细胞铺展，并同时减弱对限制敏感的细胞散射。据我们所知，这个新的多尺度模型整合了分子黏附动力学、亚细胞力、细胞变形和ECM的宏观力学特性，以预测确定形状和大小的细胞簇的状态。我们模型所做的预测不仅与许多实验设置的实验结果相符，还为理解机械敏感细胞散射和EMT提供了一个新的概念框架。
