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Sci. Signal., 20 September 2011
Vol. 4, Issue 191, p. ra60
[DOI: 10.1126/scisignal.2002221]

RESEARCH ARTICLES

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

Hiroshi Yagi1, Wenfu Tan1*, Patricia Dillenburg-Pilla1, Sylvain Armando2, Panomwat Amornphimoltham3, May Simaan1, Roberto Weigert3, Alfredo A. Molinolo1, Michel Bouvier2, and J. Silvio Gutkind1{dagger}

1 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20852, USA.
2 Department of Biochemistry, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
3 Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20852, USA.

* Present address: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.

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 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.

{dagger} To whom correspondence should be addressed. E-mail: sg39v{at}nih.gov

Citation: H. Yagi, W. Tan, P. Dillenburg-Pilla, S. Armando, P. Amornphimoltham, M. Simaan, R. Weigert, A. A. Molinolo, M. Bouvier, J. S. Gutkind, A Synthetic Biology Approach Reveals a CXCR4-G13-Rho Signaling Axis Driving Transendothelial Migration of Metastatic Breast Cancer Cells. Sci. Signal. 4, ra60 (2011).

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