MYADM Activates RhoA-Mediated Amoeboid Migration to Drive Metastasis

Abstract Metastasis, the leading cause of cancer-related mortality, remains the most critical challenge in cancer treatment. Cancer cells can adopt amoeboid migration to facilitate metastasis, highlighting the need elucidate the molecular pathways regulating the amoeboid migration phenotype. Here, we identified that MYADM, a transmembrane protein expressed during myeloid cell maturation, enabled cancer cells to acquire amoeboid migration plasticity, promoting metastasis and contributing to poor patient outcomes. Cancer cells exploited MYADM-mediated adhesion and migration to mimic leukocyte trafficking. By interacting with RhoGDI, MYADM activated RhoA-mediated leukocyte trafficking-associated genes (LTAG) enrichment, invasiveness, membrane blebbing, and anoikis resistance. MYADM modulated chromatin accessibility (CA)-regulatory genes, influencing intermediate filament cytoskeleton dynamics of cancer cells and tumor tissues. MYADM loss in cancer cells triggered CA-driven death signaling, blocking metastasis, which was not observed in monocytes. These findings position MYADM as a potential therapeutic target to disrupt metastasis, offering avenues for clinical intervention.