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.

中文翻译：

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CDC42EP5/BORG3 调节 SEPT9 促进肌动球蛋白功能、迁移和侵袭


快速的变形虫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。这种迁移行为受到高水平肌动球蛋白收缩性的严格控制，但人们对它如何与其他细胞骨架成分结合却知之甚少。脓毒症越来越被认为是新型细胞骨架成分，但缺乏关于其调节和对迁移的贡献的详细信息。在这里，我们表明，变形虫黑色素瘤细胞侵入并迁移到富含胶原蛋白的基质以及体内局部侵入和传播始终需要脓蛋白调节剂Cdc42EP5。 Cdc42EP5 与肌动蛋白结构相关，导致肌动球蛋白收缩性增强和变形虫迁移。 Cdc42EP5 通过 SEPT9 依赖性 F-肌动蛋白交联影响这些功能，从而能够生成高度收缩性肌动球蛋白结构持续稳定所需的 F-肌动蛋白束。这项研究提供了证据，证明 Cdc42EP5 是癌细胞运动的调节因子，可协调肌动蛋白和隔膜蛋白网络，并描述了 SEPT9 在黑色素瘤侵袭和转移中的独特作用。