Max-Planck-Institute for Medical Research, Dept. of Cellular Biophysics, Stuttgart, Germany.
Department of Internal Medicine I, Ulm University, Ulm, Germany.
Sci Rep. 2017 Mar 24;7:45152. doi: 10.1038/srep45152.
The interactions between a cancer cell and its extracellular matrix (ECM) have been the focus of an increasing amount of investigation. The role of the intermediate filament keratin in cancer has also been coming into focus of late, but more research is needed to understand how this piece fits in the puzzle of cytoskeleton-mediated invasion and metastasis. In Panc-1 invasive pancreatic cancer cells, keratin phosphorylation in conjunction with actin inhibition was found to be sufficient to reduce cell area below either treatment alone. We then analyzed intersecting keratin and actin fibers in the cytoskeleton of cyclically stretched cells and found no directional correlation. The role of keratin organization in Panc-1 cellular morphological adaptation and directed migration was then analyzed by culturing cells on cyclically stretched polydimethylsiloxane (PDMS) substrates, nanoscale grates, and rigid pillars. In general, the reorganization of the keratin cytoskeleton allows the cell to become more 'mobile'- exhibiting faster and more directed migration and orientation in response to external stimuli. By combining keratin network perturbation with a variety of physical ECM signals, we demonstrate the interconnected nature of the architecture inside the cell and the scaffolding outside of it, and highlight the key elements facilitating cancer cell-ECM interactions.
癌细胞与其细胞外基质（ECM）之间的相互作用一直是研究的重点。最近，中间丝角蛋白在癌症中的作用也逐渐成为焦点，但需要更多的研究来了解这一块如何适应细胞骨架介导的侵袭和转移的难题。在侵袭性胰腺癌细胞 Panc-1 中，角蛋白磷酸化与肌动蛋白抑制联合作用足以减少两种治疗方法单独作用下的细胞面积。然后，我们分析了周期性拉伸细胞的细胞骨架中的相交角蛋白和肌动蛋白纤维，没有发现方向相关性。然后，通过在周期性拉伸的聚二甲基硅氧烷（PDMS）基底、纳米级格栅和刚性支柱上培养细胞，分析角蛋白组织在 Panc-1 细胞形态适应和定向迁移中的作用。一般来说，角蛋白细胞骨架的重组使细胞变得更加“灵活”-表现出更快、更定向的迁移和对外部刺激的定向。通过将角蛋白网络扰动与各种物理 ECM 信号相结合，我们证明了细胞内部结构和外部支架之间的互联性质，并强调了促进癌细胞-ECM 相互作用的关键要素。
