TBXA2R activates ERMs to drive motility, invasion, and metastatic colonization of TNBC cells.

Cell migration and invasion are critical for cancer cell metastasis, relying on the ability of cells to adapt their morphology. Proteins of the ezrin, radixin, and moesin (ERM) family are key regulators of cell morphogenesis and essential determinants of cancer cell metastasis. However, the mechanisms by which ERMs are activated in metastatic cells remain poorly understood. We identified the thromboxane A2 receptor (TBXA2R), a G protein-coupled receptor overexpressed in multiple cancers, as a critical activator of ERMs, enhancing the motility and invasion of triple-negative breast cancer cells. We found that TBXA2R activates ERMs by engaging the Gα(q/11) and Gα(12/13) subfamilies, the Rho subfamily of Rho GTPases, and their Ser/Thr kinase effectors SLK and LOK. Furthermore, we demonstrate that TBXA2R promotes triple-negative breast cancer cell motility and invasion in vitro and metastatic colonization in vivo, dependent on ERM function. This reveals a novel signaling axis by which a member of the largest class of receptors activates key metastatic determinants, thereby controlling various aspects of metastasis. This discovery opens new avenues for developing targeted therapies against cancer metastasis.