Cdc42EP5/BORG3 modulates SEPT9 to promote actomyosin function and melanoma invasion and metastasis

Fast amoeboid migration in the invasive fronts of melanoma is controlled by high levels of actomyosin contractility, which underlie its highly metastatic potential. How this migratory behaviour 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 cancer migration and metastasis are lacking. Here, we show that the septin regulator Cdc42EP5 is consistently required for melanoma cells to migrate and invade into collagen-rich matrices, and to locally invade and disseminate in vivo . Cdc42EP5 associates with actin structures leading to increased actomyosin contractility and amoeboid migration. Cdc42EP5 effects these functions through SEPT9-dependent F-actin crosslinking, which enables the generation of F-actin bundles required for the sustained stabilisation of highly contractile actomyosin structures. This study provides evidence for Cdc42EP5 as a regulator of cancer cell motility that coordinates actin and septin networks. It also describes a unique role for SEPT9 in invasion and metastasis, and illustrates a mechanism that regulates its function in melanoma.