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Actine : entre structure et mouvement

Abstract : Actin is involved in many physiological and pathological cellular functions. In my thesis I analyzed the role of actin i) during tumor invasion and ii) in the formation of fenestrae in liver sinusoidal endothelial cells. i) Tumor cells form actin-based structures, invadosomes, involved in extracellular matrix (ECM) degradation. My work has demonstrated that the RhoGTPase Cdc42 regulates the formation of invadosomes, while the Tks5 scaffold protein is required for the matrix degradation activity. These two molecules form a minimum molecular signature for invadosomes. We found that type I collagen, which is overexpressed in the tumor microenvironment, induces the formation of linear invadosomes (Lis). We have identified the discoidin receptor 1 (DDR1) to be specifically responsible for Lis formation. Its interaction with the fibrillar collagen allows the recruitment of GEF Tuba and the activation of Cdc42 RhoGTPase leading to Li formation. DDR1 is implicated in tumor invasion and its overexpression is a poor prognosis in many cancers like lung or breast. The DDR1 receptor is also involved in cell cohesion in the collective migration of tumor cells. We have demonstrated that in a context rich in type I collagen, DDR1 has a dual location and therefore possesses different roles in the collective migration of tumor cells: a role in cell cohesion and a role in ECM degradation. We are analyzing the role of the different DDR1 isoforms in this process. We wish subsequently to determine the molecular mechanisms that regulate the expression, localization and signaling associated with these different isoforms. ii) In a physiological context, the liver capillaries have transcellular pores that allow bidirectional exchanges between the blood and the hepatocytes to ensure the proper filtering function of that organ. During the fibrosis process, these pores are lost thus decreasing the exchanges. We have demonstrated that the loss of these “fenestrae” is reversible and also that actin does not play a role in their formation. We have developed a novel method to analyze these structures in living cells using high resolution STED microscopy. Now, by using mass spectrometry approach coupled to our new observation methods in STED, we want to validate the fenestrae co-localisation with potential markers identified.
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Submitted on : Tuesday, December 5, 2017 - 1:02:48 AM
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  • HAL Id : tel-01655502, version 1

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Julie Di Martino. Actine : entre structure et mouvement. Cancer. Université de Bordeaux, 2015. Français. ⟨NNT : 2015BORD0269⟩. ⟨tel-01655502⟩

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