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

Dillon P Boulton; Connor J Hughes; Valentina Vaira; Alessandro Del Gobbo; Alessandro Palleschi; Marco Locatelli; Etienne Danis; Masoom Raza; Andrew J Neumann; Stephen Connor Purdy; Raymundo Lerma; John Meshki; Heide L Ford; Rytis Prekeris; Colm Morrissey; M Cecilia Caino

doi:10.1016/j.celrep.2024.115120

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

Cell Rep. 2024 Dec 24;44(1):115120. doi: 10.1016/j.celrep.2024.115120. Online ahead of print.

Authors

Dillon P Boulton¹, Connor J Hughes¹, Valentina Vaira², Alessandro Del Gobbo³, Alessandro Palleschi⁴, Marco Locatelli⁵, Etienne Danis⁶, Masoom Raza⁷, Andrew J Neumann⁸, Stephen Connor Purdy⁹, Raymundo Lerma¹⁰, John Meshki⁷, Heide L Ford¹¹, Rytis Prekeris¹², Colm Morrissey¹³, M Cecilia Caino¹⁴

Affiliations

¹ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Pharmacology Graduate Program, University of Colorado, Aurora, CO 80045, USA.
² Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
³ Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
⁴ Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; Division of Thoracic Surgery and Lung Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
⁵ Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
⁶ Bioinformatics and Biostatistics Shared Resource Core, University of Colorado, Aurora, CO 80045, USA; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁷ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
⁸ Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Molecular Biology Graduate Program, University of Colorado, Aurora, CO 80045, USA.
⁹ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Cancer Biology Graduate Program, University of Colorado, Aurora, CO 80045, USA.
¹⁰ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Molecular Biology Graduate Program, University of Colorado, Aurora, CO 80045, USA.
¹¹ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
¹² Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
¹³ Department of Urology, University of Washington School of Medicine, Seattle, WA 98195, USA.
¹⁴ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: [email protected].

PMID: 39723893
DOI: 10.1016/j.celrep.2024.115120

Abstract

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.

Keywords: CP: Cancer; CP: Molecular biology; MIRO2; MYO9B; RhoA; metastasis; small GTPases; tumor cell invasion.