Tumor progression is a process in which cancer cells acquire survival, proliferation and invasion properties, leading to their dissemination and metastasis. These are the leading cause of death for cancer patients. Cells that become detached from the primary tumor enter the bloodstream where they come into contact with the platelets. These are small, anucleate cell fragments that play a central role in stopping bleeding. Platelets also participate in non-haemostatic processes, including metastatic spread. In particular, it has been shown that patients with solid cancers such as breast and colon cancer, have a high number of circulating platelets, which is associated with a poor prognosis. Studies have shown that platelets interact directly with cancer cells via an unclear mechanism. Hypotheses suggest that this interaction could allow: i) to avoid the destruction of tumor cells by the immune system and the forces of the flow, ii) their recruitment at the level of the endothelium, iii) their transmigration; iv) or that it would regulate their functions at remote sites.
The proposed thesis aims to elucidate the mechanisms involved by platelets in metastatic dissemination derived from breast and colon cancer. For this purpose, we will use mouse models of metastases, based on the orthotopic injection of mammary (E0771) or colonic (MC38) cancer cells. Primary tumor growth and pulmonary and hepatic metastases will be monitored over time using small animal imaging (non-invasive bioluminescence system). The anatomo-pathological properties of metastases will be determined by histological methods. The role of platelets will be evaluated using antiplatelet agents (aspirin, clopidrogel) and we will determine the importance of other platelet receptors (integrin β1, P2Y1, P2X1, GPVI) using transgenic animals available in the laboratory. . In parallel with this in vivo work, we will use several human and murine cancer lines (MCF7, SKRB3, E0771) to study in vitro and ex vivo, their physical and functional interaction with platelets. This will be done in suspension (flow cytometry), in static conditions or in perfusion systems. Finally, we will use intravital miscroscopy (confocal microscopy) to visualize the interactions between platelets, tumor cells and endothelial cells in the mouse (mesenteric arteriole and dorsal chamber), as well as the role of platelets in the extravasation process. . The perspectives of this work are to better understand the role of platelets in metastatic dissemination and to propose new anticancer strategies.

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