Division of Cancer Biology, The Institute of Cancer Research, London, UK.
Instituto de Biomedicina y Biotecnología de Cantabria (Consejo Superior de Investigaciones Científicas, Universidad de Cantabria), Santander, Spain.
J Cell Biol. 2020 Sep 7;219(9). doi: 10.1083/jcb.201912159.
Fast amoeboid migration is critical for developmental processes and can be hijacked by cancer cells to enhance metastatic dissemination. This migratory behavior is tightly controlled by high levels of actomyosin contractility, but how it is coupled to other cytoskeletal components is poorly understood. Septins are increasingly recognized as novel cytoskeletal components, but details on their regulation and contribution to migration are lacking. Here, we show that the septin regulator Cdc42EP5 is consistently required for amoeboid melanoma cells to invade and migrate into collagen-rich matrices and locally invade and disseminate in vivo. Cdc42EP5 associates with actin structures, leading to increased actomyosin contractility and amoeboid migration. Cdc42EP5 affects these functions through SEPT9-dependent F-actin cross-linking, which enables the generation of F-actin bundles required for the sustained stabilization of highly contractile actomyosin structures. This study provides evidence that Cdc42EP5 is a regulator of cancer cell motility that coordinates actin and septin networks and describes a unique role for SEPT9 in melanoma invasion and metastasis.
快速阿米巴样迁移对于发育过程至关重要，并且可以被癌细胞劫持以增强转移扩散。这种迁移行为受到肌动球蛋白收缩性的严格控制，但人们对其与其他细胞骨架成分的偶联方式知之甚少。栓系蛋白越来越被认为是新型细胞骨架成分，但关于其调节及其对迁移的贡献的细节尚不清楚。在这里，我们表明，栓系蛋白调节剂 Cdc42EP5 对于变形虫黑色素瘤细胞侵入和迁移到富含胶原蛋白的基质中以及在体内局部侵入和扩散是始终必需的。Cdc42EP5 与肌动蛋白结构相关联，导致肌动球蛋白收缩性和阿米巴样迁移增加。Cdc42EP5 通过 SEPT9 依赖性 F-肌动蛋白交联来影响这些功能，这使得能够产生用于持续稳定高收缩性肌动球蛋白结构的 F-肌动蛋白束。这项研究提供了证据表明，Cdc42EP5 是一种协调肌动蛋白和栓系蛋白网络的癌细胞运动调节剂，并描述了 SEPT9 在黑色素瘤侵袭和转移中的独特作用。
