Gasparski Alexander N, Ozarkar Snehal, Beningo Karen A
Department of Biological Sciences, Wayne State University, Detroit, MI 48202-3917, USA.
Department of Biological Sciences, Wayne State University, Detroit, MI 48202-3917, USA
J Cell Sci. 2017 Jun 1;130(11):1965-1978. doi: 10.1242/jcs.199760. Epub 2017 Apr 26.
Cancer cell invasion is influenced by various biomechanical forces found within the microenvironment. We have previously found that invasion is enhanced in fibrosarcoma cells when transient mechanical stimulation is applied within an mechano-invasion assay. This enhancement of invasion is dependent on cofilin (CFL1), a known regulator of invadopodia maturation. Invadopodia are actin-rich structures present in invasive cancer cells that are enzymatically active and degrade the surrounding extracellular matrix to facilitate invasion. In this study, we examine changes in gene expression in response to tugging on matrix fibers. Interestingly, we find that integrin β3 expression is downregulated and leads to an increase in cofilin activity, as evidenced by a reduction in its Ser3 phosphorylation levels. As a result, invadopodia lengthen and have increased enzymatic activity, indicating that transient mechanical stimulation promotes the maturation of invadopodia leading to increased levels of cell invasion. Our results are unique in defining an invasive mechanism specific to the invasive process of cancer cells that is triggered by tugging forces in the microenvironment, as opposed to rigidity, compression or stretch forces.
癌细胞侵袭受微环境中多种生物力学力的影响。我们之前发现，在机械侵袭试验中施加短暂的机械刺激时，纤维肉瘤细胞的侵袭能力会增强。这种侵袭增强依赖于丝切蛋白（CFL1），它是一种已知的侵袭伪足成熟调节因子。侵袭伪足是侵袭性癌细胞中富含肌动蛋白的结构，具有酶活性并降解周围的细胞外基质以促进侵袭。在本研究中，我们检测了因牵拉基质纤维而引起的基因表达变化。有趣的是，我们发现整合素β3表达下调，导致丝切蛋白活性增加，其丝氨酸3磷酸化水平降低证明了这一点。结果，侵袭伪足变长且酶活性增加，表明短暂的机械刺激促进了侵袭伪足的成熟，导致细胞侵袭水平提高。我们的研究结果独特之处在于，它定义了一种特定于癌细胞侵袭过程的侵袭机制，该机制由微环境中的牵拉力量触发，而非硬度、压缩或拉伸力量。
