title: A synthetic biology approach reveals a CXCR4-G13-Rho signaling axis driving transendothelial migration of metastatic breast cancer cells.
abstract: 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 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.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20852, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yagi
authors.forename: Wenfu
authors.initials: W
authors.lastname: Tan
authors.forename: Patricia
authors.initials: P
authors.lastname: Dillenburg-Pilla
authors.forename: Sylvain
authors.initials: S
authors.lastname: Armando
authors.forename: Panomwat
authors.initials: P
authors.lastname: Amornphimoltham
authors.forename: May
authors.initials: M
authors.lastname: Simaan
authors.forename: Roberto
authors.initials: R
authors.lastname: Weigert
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D058615:Synthetic Biology; D014183:Transplantation, Heterologous; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020741:rho GTP-Binding Proteins