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Role of blood platelets in metastatic dissemination

Research unit

UMR_S 949 - Biologie et pharmacologie des plaquettes sanguines : hémostase, thrombose, transfusion
10, rue Spielmann - BP 36 67065 Strasbourg Cedex

Group

Name: Biologie et pharmacologie des plaquettes : athérothrombose expérimentale et clinique, transfusion

Group leader: GACHET Christian - christian.gachet@efs-alsace.fr

Group leader's phone: 03.88.21.25.25

Website: Visit website

Group organization:
- Chercheurs: 5
- ITA: 5
- Doctorants: 2
- Post-Docs: 3
- Autres: 2

Publications of the team linked to the topic (3 last years):
1) Schaff M, Tang C, Maurer E, Bourdon C, Receveur N, Eckly A, Hechler B, Arnold C, de Arcangelis A, Nieswandt B, Denis CV, Lefebvre O, Georges-Labouesse E, Gachet C, Lanza F, Mangin PH. 2013. Integrin α6β1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis. Circulation. 128(5):541-52.
2) Maurer E, Tang C, Schaff M, Bourdon C, Receveur N, Ravanat C, Eckly A, Hechler B, Gachet C, Lanza F, Mangin PH. 2013. Targeting platelet GPIbβ reduces platelet adhesion, GPIb signaling and thrombin generation and prevents arterial thrombosis. Arterioscler Thromb Vasc Biol. 33(6):1221-9.
3) Schaff M, Receveur N, Bourdon C, Wurtz V, Denis CV, Orend G, Gachet C, Lanza F, Mangin PH. 2011. Novel function of tenascin-C, a matrix protein relevant to atherosclerosis, in platelet recruitment and activation under flow. Arterioscler Thromb Vasc Biol. 31(1):117-24.

About PhD

PhD Director: MANGIN Pierre - pierre.mangin@efs-alsace.fr

Phone: 03.88.21.25.25

Junior advisor: non

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Role of blood platelets in metastatic dissemination

Project: During cancer progression, tumor cells acquire survival, proliferative and invasive properties which lead to their dissemination and metastasis formation. Metastasis is the main cause of mortality in patients suffering from cancer. Cells detach from the primary tumor, enter in the blood stream where they get in contact with platelets. Blood platelets are small anucleated cells playing a key role in the arrest of bleeding. In addition, they are also involved in non-hemostatic functions including metastatic dissemination. Several clinical studies have established a link between platelets and tumor progression. Clinical trials have suggested that aspirin administered at antiplatelet doses reduces metastatis. Moreover, an elevated platelet count, called thombocytosis, is a bad prognosis for patients with a breast or colon cancer. Finally, cancer patients can present life-threatening thrombosis. Beside, several in vitro studies suggest that platelets directly interact with tumor cells through a mechanism that remains to be established. Several hypotheses were proposed concerning this interaction which could allow cancer cells to escape immune surveillance, recruit these cells at the endothelium, allow their transmigration or regulate their functions at distant sites.
The aim of this phD is to unravel the mechanisms by which platelets participate in metastatic dissemination of breast and colon cancer. The progression and metastatic formation of these cancers will be assessed by using mice with various platelet counts (low: Mpl-/-: 80X103 plt/µL; normal: WT: 106 plt/µL; and elevated: overexpression of Mpl: 5X106plt/µL). The models will be based on orthotopic injection of breast (E0771) and colon (MC38) cancer cells. In addition, we will develop a model of immune thrombocytopenia by injecting an anti-platelet antibody (R300) to WT mice. Tumor growth and metastatic formation will be followed over time by bioluminescence imaging on the whole mouse body. Anatopathological properties of the metastasis will be determined by histological methods. In parallel, we will evaluate the effect of antiplatelet agents (aspirine, clopidrogel) on metastatic formation of breast and colon cancer and determine the role of several platelet receptors (β1 integrins, P2Y1, P2X1) by using genetically modified mice. In addition to this in vivo work, we will use numerous human and mouse cancer cell lines (MCF7, SKRB3, HT29, E0771…) to study in vitro and ex vivo their physical and functional interaction with platelets. These experiments will be performed in suspension (flow cytometry) and static and flow conditions. The perspectives of this work are to better understand the role of platelets in metastatic formation and to propose novel anticancer strategies.

Wished skills: Dynamism, self-motivation, scientific rigor - Basic knowledge in cell biology

Expertises which will be acquired during the training: General knowledge in platelet biology, in thrombosis and cancer. Technical expertise in cell biology and various microscopy techniques (wide field, epi-fluorescence, confocal microscopy) as well as in various in vivo models.