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Etude de l'influence du PAI-1 matriciel sur la régulation de la transition Mésenchymo-Amiboïde des cellules cancéreuses

Abstract : The Mesenchymal-Amoeboid transition (MAT) is required for metastatic escape, however it has not been associated with a precise physiopathological requirement yet. PAI-1, type-1 plasminogen activator inhibitor, is a tumor matrix molecule considered as marker of bad prognosis and found in high amount in the most aggressive tumors. We show that, in its activated matrix form, PAI-1 is able to maintain, in time and with concentration-dependence, the amoeboid morphology of colorectal and mammary cancer cells, and that this one is associated with a weak integrin-independant adhesion, an amoeboid migration and the activation of RhoA/ROCK-1/MLC-P pathway. The involved molecular mechanism has been partially underlined: we show that immobilization of PAI-1 and its link with uPA are essential, and we assume that the membrane receptor uPAR participates in the transmission of signals maintaining activated the RhoA/ROCK-1/MLC-P pathway. The compatibility of matrix PAI-1 effects towards the main signaling pathways involved in MAT regulation is established in silico with a method based on the modeling of interaction network dynamics. All this results enable for the first time to characterize a matrix physiopathological situation supporting MAT; and although the matrix form of PAI-1 has not been revealed all its secrets yet, it seems to be an interesting therapeutic target.
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Amandine Cartier-Michaud. Etude de l'influence du PAI-1 matriciel sur la régulation de la transition Mésenchymo-Amiboïde des cellules cancéreuses. Biologie cellulaire. Université d'Evry-Val d'Essonne, 2010. Français. ⟨tel-00875713⟩

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