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A Synthetic Biology Approach Reveals a CXCR4-G13-Rho Signaling Axis Driving Transendothelial Migration of Metastatic Breast Cancer Cells

Interfering with a specific G protein–coupled receptor pathway may provide a therapeutic approach to blocking metastasis of some forms of breast cancer. Blocking Malignant Spread Most deaths from cancer arise from the metastatic spread of malignant cells rather than from growth of the primary tumor itself. Thus, identifying the mechanisms whereby metastasis occurs—and thereby potential approaches to blocking it—represents a crucial element of cancer research. Noting that the chemokine receptor CXCR4 [chemokine (C-X-C motif) receptor 4], which mediates trafficking of hematopoietic cells, has been implicated in breast cancer metastasis, Yagi et al. explored the underlying mechanisms. They found that the CXCR4-mediated migration toward chemokine of a therapy-resistant class of breast cancer cell, unlike its mobilization of hematopoietic stem cells, depended on signaling through Gα13 of the Gα12/13 family of G proteins and of the small guanosine triphosphatase Rho. Moreover, fasudil, a Rho inhibitor now used to treat vasospasm and pulmonary hypertension, limited breast cancer metastasis from lymph nodes in a mouse model system. Thus, interfering with CXCR4-Gα13-Rho signaling may provide a therapeutic approach to blocking metastasis of this class of breast cancer without untoward side effects on the mobilization and migration of hematopoietic cells. Tumor cells can co-opt the promigratory activity of chemokines and their cognate G protein–coupled receptors (GPCRs) to metastasize to regional lymph nodes or distant organs. Indeed, the migration 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 Gα13, a member of the Gα12/13 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-Gα13-Rho axis prevents the metastatic spread of basal-like breast cancer cells.