Cdc42EP5/BORG3 coordinates septin and actin networks to promote actomyosin function and melanoma invasion and metastasis

Abnormal cell migration and invasion underlie metastatic dissemination in cancer and require substantial cytoskeletal rearrangements. Although septins are increasingly recognised as novel cytoskeletal components, 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 and promotes their rearrangement, leading to increased actomyosin contractility, rounded/amoeboid behaviours and focal adhesion maturation. Cdc42EP5 effects these functions through the modulation of the septin cytoskeleton and we show a unique role for SEPT9 in controlling actomyosin contractility, invasion and metastasis in melanoma. This study provides unprecedented evidence for Cdc42EP5 as a new type of regulator of cancer cell motility that coordinates actin and septin networks to enable the generation of a higher contractile cytoskeleton. It also highlights the differential role of individual septins in invasion and metastasis, and illustrates a mechanism that regulates their function in cancer.