Journal
JOURNAL OF CELL BIOLOGY
Volume 199, Issue 4, Pages 653-668Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201205169
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Funding
- Cancer Research UK
- Biotechnology and Biological Sciences Research Council
- Breast Cancer Campaign
- King's College London British Heart Foundation Centre of Excellence
- Association for International Cancer Research
- Bettencourt-Schueller Foundation
- European Molecular Biology Organization (EMBO)
- Graduate Program in Areas of Basic and Applied Biology (GABBA) PhD scholarship (Portugal)
- Royal Society University Research Fellowship
- BBSRC [BB/E004083/1, BB/E004083/2] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E004083/1, BB/E004083/2] Funding Source: researchfish
- Cancer Research UK [11563] Funding Source: researchfish
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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. 1 integrin expression at the transcriptional level via the transcription factor serum response factor (SRF). beta 1 integrin is the main target for Cdc42-mediating interaction of cancer cells with endothelial cells and the underlying extracellular matrix, as exogenous. 1 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. 1 integrin as a transcriptional target of Cdc42, our results provide new insight into Cdc42 function.
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