The G protein-coupled receptor TBXA2R activates ERMs to promote motility, invasion, and metastasis of triple-negative breast cancer cells

Abstract

ABSTRACTMetastasis, the process by which cancer cells colonize distant organs, relies on the ability of these cells to migrate and invade the surrounding tissues. The ezrin, radixin, and moesin family (ERM) of proteins are critical regulators of cell morphology transformations required for cancer cell movement and invasion. Yet, how ERMs are activated during metastasis remains poorly understood. Here, we identified the thromboxane A2 receptor (TBXA2R), a G protein-coupled receptor, as a critical activator of ERMs that promotes motility, invasion, and metastasis of triple-negative breast cancer (TNBC) cells. We found that ERM activation downstream of TBXA2R signaling depends on the Gαq/11and Gα12/13subfamilies, the small GTPase RhoA, and its Ser/Thr kinase effector SLK. We also showed that TBXA2R signaling increases TNBC cell motility and invasionin vitroand metastasisin vivo,depending on ERMs. These findings unveil a novel mechanism by which a member of the largest class of receptors activates key metastatic determinants to promote TNBC metastasis, which could have important implications for developing novel therapeutic strategies.