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.
Authors
- Valentina Vaira (ORCID: https://orcid.org/0000-0003-4416-6216)
- Masoom Raza
- Alessandro Del Gobbo
- Colm M. Morrissey (ORCID: https://orcid.org/0000-0003-1906-5333)
- Dillon P. Boulton (ORCID: https://orcid.org/0000-0002-7781-3101)
- Heide L. Ford (ORCID: https://orcid.org/0000-0002-2860-9841)
- A. Palleschi (ORCID: https://orcid.org/0000-0003-4510-5167)
- Marco Locatelli (ORCID: https://orcid.org/0000-0003-0778-3653)
- Etienne Danis (ORCID: https://orcid.org/0000-0002-5651-8111)
- Connor J. Hughes (ORCID: https://orcid.org/0000-0001-6295-8167)
- Rytis Prekeris (ORCID: https://orcid.org/0000-0003-3393-1963)
- M. Cecilia Caino (ORCID: https://orcid.org/0000-0001-8294-8070)
- Andrew J. Neumann (ORCID: https://orcid.org/0000-0002-4809-6289)
- Stephen C. Purdy (ORCID: https://orcid.org/0000-0001-9640-5501)
- John Meshki
- Raymundo Lerma
Institutions
- University of Washington (US)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- University of Colorado Cancer Center (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-12-24
- DOI
- https://doi.org/10.1016/j.celrep.2024.115120
- Citations
- 4
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- U.S. Department of Defense
- Boettcher Foundation
- University of Washington
- National Institutes of Health
- Cancer Center, University of Colorado
- National Cancer Institute