Cancer biology: A synthetic biology approach reveals a CXCR4-G ₁₃-rho signaling axis driving transendothelial migration of metastatic breast cancer cells

Tumor cells can co-opt the promigratory activity of chemokines and their cognate G protein-coupled receptors (GPCRs) tometastasize to regional lymph nodes or distant organs. Indeed, themigration toward SDF-1 (stromal cell-derived factor 1) of tumor cells bearing CXCR4 [chemokine (C-X-C motif) receptor 4] has been implicated in the lymphatic and organ-specific metastasis of various human malignancies. Here, we used chimeric G proteins and GPCRs activated solely by artificial ligands to selectively activate the signaling pathways downstream of specific G proteins and showed that CXCR4-mediated chemotaxis and transendothelial migration of metastatic basal-like breast cancer cells required activation of Gα ₁₃, a member of the Gα _12/13 G protein family, and of the small guanosine triphosphatase Rho. Multiple complementary experimental strategies, including synthetic biology approaches, indicated that signaling-selective inhibition of the CXCR4- Gα ₁₃-Rho axis prevents the metastatic spread of basal-like breast cancer cells.