We demonstrate the relative roles of the cell cytoskeleton, and specific importance of actin in facilitating mechanical aspects of metastatic invasion. A crucial step in metastasis, the typically lethal spread of cancer to distant body-sites, is cell invasion through dense tissues composed of extracellular matrix and various non-cancerous cells. Cell invasion requires cell-cytoskeleton remodeling to facilitate dynamic morphological changes and force application. We have previously shown invasive cell subsets in heterogeneous samples can rapidly (2 h) and forcefully indent non-degradable, impenetrable, synthetic gels to cell-scale depths. The amounts of indenting cells and their attained depths provide the mechanical invasiveness of the sample, which as we have shown agrees with the in vitro metastatic potential and the in vivo metastatic risk in humans. To identify invasive force-application mechanisms, we evaluated changes in mechanical invasiveness following chemical perturbations targeting the structure and function of cytoskeleton elements and associated proteins. We evaluate effects on short-term (2-hr) indentations of single, well-spaced or closely situated cells as compared to long-time-scale Boyden chamber migration. We show that actomyosin inhibition may be used to reduce (mechanical) invasiveness of single or collectively invading cells, while actin-disruption may induce escape-response of treated single-cells, which may promote metastasis.

我们证明了细胞骨架的相对作用，以及肌动蛋白在促进转移性侵袭的机械方面的特殊重要性。转移的关键步骤，通常是癌症向远处身体部位的致命扩散，是细胞侵入由细胞外基质和各种非癌细胞组成的致密组织。细胞侵袭需要细胞-细胞骨架重塑，以促进动态形态变化和力的应用。我们之前已经表明，异质样本中的侵入性细胞亚群可以快速（2 小时）并有力地将不可降解、不可穿透的合成凝胶缩进到细胞级深度。缩进细胞的数量及其达到的深度提供了样品的机械侵入性，正如我们所显示的，这与体外转移潜能和人体体内转移风险。为了确定侵入力应用机制，我们评估了针对细胞骨架元件和相关蛋白质的结构和功能的化学扰动后机械侵入性的变化。我们评估了与长期规模的博伊登室迁移相比，对单个、间隔良好或位置紧密的细胞的短期（2 小时）压痕的影响。我们表明，肌动球蛋白抑制可用于减少单个或集体入侵细胞的（机械）侵袭性，而肌动蛋白破坏可能会诱导处理过的单细胞的逃逸反应，这可能会促进转移。