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Place de la signalisation Hippo dans l'histoire naturelle du Mésothéliome Pleural Malin (MPM) : dissection de ses rôles dans les lignées mésothéliales pleurales humaines et application à la caractérisation moléculaire des 448 patients atteints de MPM inclus dans l'essai clinique de phase 3 "MAPS"

Abstract : Malignant pleural mesothelioma (MPM) is a rare, very aggressive, primary tumor with a poor prognosis. During this thesis, we wanted to identify new biomarkers of MPM by testing the influence of the RASSF/Hippo pathway inactivation on the survival of the 448 patients included in the clinical trial MAPS (IFCT- GFPC-0701). We also wanted to understand which functions and signals essential to cellular homeostasis, linked to RASSF/Hippo signaling pathway, are disturbed during the mesothelial cell transformation process. Inactivation of RASSF/Hippo members was studied by methylation-specific PCR (MS-PCR) and their influence on the survival of the 448 patients included in the MAPS clinical trial tested in uni- and multivariate analysis before being validated by bootstrap. We also mimed in cell, by RNA interference, several members of the Hippo pathway inactivation in human mesothelial cells lines (MSTO-211H, H2452, H28 and H2052). We have identified several biomarkers of MPM: i) MST1 kinase whose inactivation is a factor of poor prognosis, ii) amphiregulin whose cytoplasmic expression is on the contrary a factor of good prognosis and finally iii) CD44 whose high expression is a diagnostic tool for MPM. In cell we demonstrate that RASSF/Hippo pathway alterations induce an inappropriate activity of YAP, one Hippo end effector: the poorer prognosis of patients with inactivation of MST1 is thus explained by the fact that, by regulating YAP activity, MST1 controls the apoptosis/proliferation balance and prevents invasion and growth without adhesion from mesothelial cells. In its absence, these cellular processes are deregulated. This work finally demonstrates the importance of the CD44/RASSF1A/MST1 axis in controlling appropriate YAP activity and mesothelial cell homeostasis. The understanding of the cellular disorders induced by the of the RASSF/Hippo pathway deregulation designates YAP as a potential therapeutic target in patients with MPM and presenting alterations of this signaling pathway.
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Elodie Chevalier. Place de la signalisation Hippo dans l'histoire naturelle du Mésothéliome Pleural Malin (MPM) : dissection de ses rôles dans les lignées mésothéliales pleurales humaines et application à la caractérisation moléculaire des 448 patients atteints de MPM inclus dans l'essai clinique de phase 3 "MAPS". Biologie cellulaire. Normandie Université, 2018. Français. ⟨NNT : 2018NORMC405⟩. ⟨tel-02097491⟩

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