Journal
SCIENCE SIGNALING
Volume 4, Issue 191, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2002221
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Funding
- Gutkind labs
- Bouvier lab
- NIH, National Institute of Dental and Craniofacial Research
- Intramural AIDS Targeted Antiviral Program
- Canadian Institutes for Health Research [FRN-10501]
- Research Chair in Cell Signalling and Molecular Pharmacology
- Ministry of Research and Technology from France
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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 G alpha(13), a member of the G alpha(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-G alpha(13)-Rho axis prevents the metastatic spread of basal-like breast cancer cells.
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