title: Cdc42 promotes transendothelial migration of cancer cells through β1 integrin.
abstract: Cancer cells interact with endothelial cells during the process of metastatic spreading. Here, we use a small interfering RNA screen targeting Rho GTPases in cancer cells to identify Cdc42 as a critical regulator of cancer cell-endothelial cell interactions and transendothelial migration. We find that Cdc42 regulates β1 integrin expression at the transcriptional level via the transcription factor serum response factor (SRF). β1 integrin is the main target for Cdc42-mediating interaction of cancer cells with endothelial cells and the underlying extracellular matrix, as exogenous β1 integrin expression was sufficient to rescue the Cdc42-silencing phenotype. We show that Cdc42 was required in vivo for cancer cell spreading and protrusion extension along blood vessels and retention in the lungs. Interestingly, transient Cdc42 depletion was sufficient to decrease experimental lung metastases, which suggests that its role in endothelial attachment is important for metastasis. By identifying β1 integrin as a transcriptional target of Cdc42, our results provide new insight into Cdc42 function.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, England, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Reymond
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Im
authors.forename: Ritu
authors.initials: R
authors.lastname: Garg
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Vega
authors.forename: Barbara
authors.initials: B
authors.lastname: Borda d'Agua
authors.forename: Philippe
authors.initials: P
authors.lastname: Riou
authors.forename: Susan
authors.initials: S
authors.lastname: Cox
authors.forename: Ferran
authors.initials: F
authors.lastname: Valderrama
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Ridley
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D021381:Protein Transport; D026362:Serum Response Factor / Q000378:metabolism; D014158:Transcription, Genetic; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000172:deficiency / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; D026362:Serum Response Factor; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein