MYADM drives RhoA-dependent amoeboid plasticity and chromatin remodeling to promote metastasis

Metastasis relies on the ability of cancer cells to adopt amoeboid migration, yet the upstream regulators of this highly plastic phenotype remain incompletely defined. We identified MYADM, a transmembrane protein normally expressed during myeloid maturation, as a central driver of amoeboid migration and metastatic competency. Cancer cells hijack MYADM to mimic leukocyte-like trafficking, enabling RhoGDI interaction and RhoA activation, which induce leukocyte trafficking-associated genes, membrane blebbing, invasiveness, and anoikis resistance. Multi-omics profiling further revealed that MYADM remodels chromatin accessibility (CA) to control intermediate filament dynamics and establish a pro-metastatic transcriptional state. Loss of MYADM activates CA-driven cell-death pathways and completely suppresses metastasis-an effect selective for cancer cells but not monocytes. These results identify MYADM as a master regulator linking RhoA signaling, cytoskeletal plasticity, and chromatin remodeling, and establish MYADM inhibition as a promising therapeutic strategy to block amoeboid migration and metastatic progression.