MIRO2 promotes cancer invasion and metastasis via MYO9B suppression of RhoA activity

Metastasis to vital organs remains the leading cause of cancer-related deaths, emphasizing an urgent need for actionable targets in advanced-stage cancer. The role of mitochondrial Rho GTPase 2 (MIRO2) in prostate cancer growth was recently reported; however, whether MIRO2 is important for additional steps in the metastatic cascade is unknown. Here, we show that knockdown of MIRO2 ubiquitously reduces tumor cell invasion in vitro and suppresses metastatic burden in prostate and breast cancer mouse models. Mechanistically, depletion of MIRO2’s binding partner—unconventional myosin 9B (MYO9B)—reduces tumor cell invasion and phenocopies MIRO2 depletion, which in turn results in increased active RhoA. Furthermore, dual ablation of MIRO2 and RhoA fully rescues tumor cell invasion, and MIRO2 is required for MYO9B-driven invasion. Taken together, we show that MIRO2 supports invasion and metastasis through cooperation with MYO9B, underscoring a potential targetable pathway for patients with advanced disease. [Display omitted] •MIRO2 supports the metastatic potential of breast and prostate epithelial cancer cells•MIRO2 forms a complex with MYO9B and RhoA and suppresses RhoA activity•MYO9B-dependent cell invasion requires its GAP activity and MIRO2 expression•RhoA knockdown restores cell invasion of MIRO2-depleted cancer cells Boulton et al. report that MIRO2 is required for breast and prostate cancer invasion and metastasis. This role is mediated via interaction with MYO9B and repression of RhoA activation. This signaling may be relevant in patients, as higher MIRO2 expression is associated with downregulation of RhoA-specific genes.