Cancer cell migration requires that cells respond and adapt to their surroundings. In the absence of extracellular matrix cues, cancer cells will undergo a mesenchymal to ameboid transition, whereas a highly confining space will trigger a switch to "leader bleb-based" migration. To identify oncogenic signaling pathways mediating these transitions, we undertook a targeted screen using clinically useful inhibitors. Elevated Src activity was found to change actin and focal adhesion dynamics, whereas inhibiting Src triggered focal adhesion disassembly and blebbing. On non-adherent substrates and in collagen matrices, amoeboid-like, blebbing cells having high Src activity formed protrusions of the plasma membrane. To evaluate the role of Src in confined cells, we use a novel approach that places cells under a slab of polydimethylsiloxane (PDMS), which is held at a defined height. Using this method, we find that leader bleb-based migration is resistant to Src inhibition. High Src activity was found to markedly change the architecture of cortical actomyosin, reduce cell mechanical properties, and the percentage of cells that undergo leader bleb-based migration. Thus, Src is a signal transducer that can potently influence transitions between migration modes with implications for the rational development of metastasis inhibitors.

中文翻译：

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癌细胞运动模式不同地需要c-Src活性。

癌细胞迁移需要细胞做出反应并适应周围环境。在没有细胞外基质提示的情况下，癌细胞将经历间充质到类淀粉样细胞的过渡，而高度封闭的空间将触发向“基于前导泡的”迁移的转变。为了确定介导这些过渡的致癌信号通路，我们使用临床上有用的抑制剂进行了有针对性的筛选。发现升高的Src活性改变肌动蛋白和粘着斑动态，而抑制Src则引发粘着斑的分解和起泡。在非粘附基质上和胶原蛋白基质中，具有高Src活性的类氨气样起泡细胞形成了质膜的突起。为了评估Src在受限细胞中的作用，我们使用一种新颖的方法将细胞置于聚二甲基硅氧烷（PDMS）的平板下，该平板保持在确定的高度。使用此方法，我们发现基于前导气泡的迁移对Src抑制具有抗性。发现高的Src活性会显着改变皮质肌动球蛋白的结构，降低细胞的机械特性，以及经历基于前导的基于泡的迁移的细胞的百分比。因此，Src是一种信号传感器，可以有效影响迁移模式之间的过渡，对转移抑制剂的合理开发产生影响。以及经历基于前导气泡的迁移的细胞百分比。因此，Src是一种信号传感器，可以有效影响迁移模式之间的过渡，对转移抑制剂的合理开发产生影响。以及经历基于前导气泡的迁移的细胞百分比。因此，Src是一种信号传感器，可以有效影响迁移模式之间的过渡，对转移抑制剂的合理开发产生影响。