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Rôles des microparticules dans l'initiation et la régulation des processus de thromboses et de métastases
Funder: French National Research Agency (ANR)Project code: ANR-09-JCJC-0053

The association between the development of metastases and the risk of thrombotic complications has been documented a long time ago. Armand Trousseau was the first in 1865 to establish a direct correlation between thrombophlebitis and development of cancers. Since that time, the close relationship linking cancer, metastasis and thrombosis has been the focus of several studies. Kaplan et al. have recently developed a new concept named formation of 'premetastatic niches' to describe how a cancer cell will leave its primary tumor location to reach a secondary site where it will form a metastasis. The authors proposed that cancer cells secrete pro-metastatic factors that were found in plasma of tumor bearing animals. Recent clinical publications have demonstrated the presence in blood circulation of patients suffering from cancer of tissue factor bearing microparticles. The authors suggest that these microparticles are directly responsible for the development of a procoagulant state. However, the origin of these microparticles and their direct involvement in thrombosis and metastasis processes are to date unknown. We hypothetise that tissue factor bearing microparticles produced by cancer cells play a key role in both formations of a thrombotic state and of pre-metastatic niches. To solve that problematic we will performed in vitro experiments, used animal models and state of the art techniques of digital real time intravital microcopy that we recently import from the US to our current laboratory. Our first results, currently in revision in JEM, show that mice show that human and mice pancreatic cancer cells produce microparticles expressing tissue factor and PSGL-1. In vivo, cancer cell-derived microparticles, but not their parental cells, infused into a living mouse accumulate at the site of injury and reduce both the tail bleeding time and the time to occlusion of veins and arteries. This thrombotic state is also observed in mice developing a tumor. In such mice, cancer cell-derived microparticles shed from the growing tumor are able to enter the circulation and accumulate at the site of injury. Infusion of a blocking P-selectin antibody inhibits the interaction of cancer cell-derived microparticles with platelets and abolishes the thrombotic state observed both after injection of microparticles or when mice developed a tumor. We will now continue to focus on a mouse model of tumor induced by different pancreatic neoplasic cells. One of our first aims will be to continue to identify in vitro proteins, such as PSGL-1, potentially involved in thrombosis and/or adhesion processes and expressed on the surface of neoplasic cells derived microparticles. These proteins may play a critical role in activation/aggregation of platelets and formation of the premetastatic niches by interacting with (activated) endothelial cells. Based on our preliminary results and on current scientific literature we will focus on tissue factor (TF) but also, its main inhibitor, tissue factor pathway inhibitor (TFPI) and its recently described regulator, the protein disulfide isomerase, PDI. The presence and role(s) of the oncoisoforrm of the Bile salt dependent lipase (BSDL) will also be studied. Indeed, we reported, few months ago, that BSDL could interact via its V3 like loop structure with the chemokine receptor CXCR4, receptor known to play an important role in development of metastasis. Last, the roles of adhesive proteins (Fibronectin, integrin '2'1, P-selectin/PSGL1) or coagulant proteins (Urokinase Pathway Activator (UPA) and its receptor, UPAR) will be determined. Parallel to this work we will used our intravital microscope to set up mice models in which, endogenous and exogenous microparticles derived cancer cells, endogenous or exogenous cancer cells, endogenous platelets and endothelium will all be specifically detected and image in vivo. The main goal of this part is to confirm our initial observation that cancer derived microparticles are involved in thrombosis and metastasis processes by following and imaging in real time in vivo interactions between the different partners. Last, once we have identified proteins expressed on microparticles and set up our models we will confirm, using siRNA or blocking antibodies, in vivo the role played by these proteins and will dissect molecular mechanisms involved in thrombosis and metastasis. To perform this project we will actively used the expertise of people present in our current laboratory (INSERM UMR 911) that focus on pancreatic cancer since more than a decade. We will also use the resources (intravital microscopy, electron microscopy'), and the world recognized expertise of people present on site (collaboration with Prof. Francoise Dignat-George). Our ultimate goal is to identify new target(s) of clinical interest to limit both the development of a thrombotic state and the formation of metastasis.

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