Objective Metastasis accounts for 90% of cancer deaths, and it is therefore important and timely to identify new therapeutic targets aimed specifically at metastasis. Cdc42 has recently been implicated in a key step of the metastatic cascade: the extravasation of circulating tumour cells, also termed transendothelial migration (TEM) . This project aims to study how Cdc42 contributes to breast cancer cell TEM in vitro and in vivo. Cdc42 regulates β1‐integrin expression via the transcription factor serum response factor (SRF) and thereby stimulates cancer cell adhesion to endothelial cells (ECs) and TEM. To analyse the molecular basis for this regulation, downstream targets of Cdc42 will be depleted by RNAi in a panel of breast cancer cells to determine which target/s are responsible for altering β1‐integrin expression, adhesion to ECs or TEM.Cancer cells interact with platelets as soon as they enter the bloodstream, and this enhances cancer cell TEM in vivo. It is therefore possible that Cdc42 regulates attachment to platelets as well as ECs. The role of Cdc42 in the interaction between platelets and cancer cells will be tested by adding purified platelets to control or Cdc42‐depleted breast cancer cells in vitro and analysing platelet aggregation around cancer cells by confocal microscopy. The role of Cdc42 in platelet attachment to cancer cells during early lung colonization in vivo will be studied by intravenous injection of fluorescently tagged breast cancer cells in mice.This project will increase our understanding of metastasis. The identification of molecular targets involved in cancer cell extravasation will provide a starting point for the development of new drugs, thus contributing to reduce the mortality of patients with metastasis. Fields of science medical and health sciencesclinical medicineoncologyprostate cancernatural sciencesbiological sciencescell biologymedical and health sciencesclinical medicineoncologybreast cancernatural sciencesphysical sciencesopticsmicroscopyconfocal microscopynatural sciencesbiological sciencesgeneticsRNA Keywords Rho GTPases integrins Cdc42 cell adhesion endothelial cells breast cancer transendothelial migration cytoeskeleton platelets Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2014 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator KING'S COLLEGE LONDON Net EU contribution € 183 454,80 Address Strand WC2R 2LS London United Kingdom See on map Region London Inner London — West Westminster Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
