Cdc42Adhere · Role of Cdc42 in cancer cell adhesion to endothelial cells and platelets
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-05-11 → 2017-05-10
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Role of Cdc42 in cancer cell adhesion to endothelial cells and platelets
The process by which cancer spreads from its initial location to distant locations in the body is called metastasis. Unfortunately, when cancers spread from one part of the body to another, they are difficult to cure. It is well known that most deaths from prostate and breast cancers are due to the spread of cancer cells to different parts of the body, including bone, lung and brain. Therefore it is important to identify new cancer treatments aimed specifically at reducing metastasis. When cancers spread by metastasis, tumour cells get into the blood vessels, which carry them to other sites in the body. If the cancer cells attach to the blood vessel wall, they can get out of the blood vessels and grow to form a secondary tumour, or metastasis. When cancer cells are in the bloodstream, tiny cells called platelets stick to the cancer cells. The normal function of platelets is to clot the blood when blood vessels are cut. Platelets see the cancer cells as a ‘cut’ and clot around them. The platelets then help the cancer cells to attach to the blood vessel walls, leading to metastasis. Our research aimed to find out how prostate and breast cancer cells stick to both platelets and blood vessels walls. We discovered that three different genes in cancer cells have a role in the attachment of tumour cells to blood vessel walls. These genes are called FMNL1, FMNL2 and FMNL3. We hope this will contribute to increase the knowledge about the development of metastasis and thus bring us closer to improve the management of breast and prostate cancer metastasis.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- KING'S COLLEGE LONDON · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union