Abstract 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. Citation Format: Tai-Lung Cha, Yi-Ta Tsai, En-Ting Liu. MYADM drives RhoA-dependent amoeboid plasticity and chromatin remodeling to promote metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6100.
Cha et al. (Fri,) studied this question.