Soft tissue tumors, including breast cancer, become stiffer throughout disease progression. This increase in stiffness has been shown to correlate to malignant phenotype and epithelial-to-mesenchymal transition (EMT) in vitro. Unlike current models, utilizing static increases in matrix stiffness, our group has previously created a system that allows for dynamic stiffening of an alginate–matrigel composite hydrogel to mirror the native dynamic process. Here, we utilize this system to evaluate the role of matrix stiffness on EMT and metastasis both in vitro and in vivo. Epithelial cells were seen to lose normal morphology and become protrusive and migratory after stiffening. This shift corresponded to a loss of epithelial markers and gain of mesenchymal markers in both the cell clusters and migrated cells. Furthermore, stiffening in a murine model reduced tumor burden and increased migratory behavior prior to tumor formation. Inhibition of FAK and PI3K in vitro abrogated the morphologic and migratory transformation of epithelial cell clusters. This work demonstrates the key role extracellular matrix stiffening has in tumor progression through integrin signaling and, in particular, its ability to drive EMT-related changes and metastasis.

中文翻译：

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动态细胞外基质硬化诱导表型转化和上皮细胞迁移。

软组织肿瘤，包括乳腺癌，在整个疾病进展过程中变得更加僵硬。这种刚度的增加已被证明与体外恶性表型和上皮间质转化 (EMT) 相关。与目前的模型不同，利用基质刚度的静态增加，我们小组之前已经创建了一个系统，该系统允许藻酸盐-基质凝胶复合水凝胶的动态硬化以反映天然动态过程。在这里，我们利用该系统来评估基质刚度对体外和体内EMT 和转移的作用. 观察到上皮细胞失去正常形态并在变硬后变得突出和迁移。这种转变对应于细胞簇和迁移细胞中上皮标志物的丢失和间充质标志物的增加。此外，小鼠模型中的硬化减少了肿瘤负荷并增加了肿瘤形成前的迁移行为。体外FAK 和 PI3K 的抑制消除了上皮细胞簇的形态学和迁移转化。这项工作表明的关键作用的细胞外基质变硬通过整信令和，特别地，它能够驱动EMT相关的变化在肿瘤进展小号和转移。