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Impact de la matrice extracellulaire sur la migration des cellules souches de glioblastome : un modèle tridimensionnel de culture et une nouvelle stratégie thérapeutique

Abstract : Glioblastoma Multiforme (GBM) is a biologically aggressive tumor with an extremely poor prognosis. The highly invasive capacity of a subpopulation of Glioblastoma Initiating Cells (GIC) makes complete surgical resection impossible. GBM dissemination occurs along preexisting brain structures such as the perivascular space rich in laminin, fibronectine and collagen as well as the aligned myelinated fibers of the corpus callosum. The Extracellular Matrix (ECM) of these cerebral regions plays an important role during GBM invasion, but the underlying mechanisms remain largely unknown. Accordingly, the development of new anti-migratory therapies targeting the cell-ECM interactions is lacking. In order to mimic the compositional and physical properties of the cerebral ECM and to investigate their role(s) in GBM invasion, we have set up a new aligned nanofibers (NF)scaffold functionalized with laminin. My work demonstrated that the NFs constitute a tridimensional (3D) microenvironment supporting GIC adhesion and migration. The cell-ECM adhesion is improved on the NF in comparison to the conventional 2D planar surfaces (PS). Furthermore, the mechanisms of GIC interaction with the ECM on the NF are similar to those observed in the human GBM xenograft murine model. In this physiologically more relevant 3D microenvironment reproduced by the NF, the variation of the different biochemical and mechanical components of the ECM affects the migration of GIC. The presence or absence of laminin on the NF regulates the mode of migration and the orientation of the fibers dictates the direction of migration of GIC. On the other hand, the glycosylation that decorates cell surface proteins modulates the interaction of GBM tumor cells with the ECM and its alteration increases their invasion. The second part of my thesis demonstrated that the glycomimetics phostines « 3.1a » remodel the N-glycosylation of GIC and decrease their invasivity in vitro and in vivo via the inhibition of FAK and TGFβ-R signaling pathways known to be implicated in the cell-ECM intercommunication.
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Ali Saleh. Impact de la matrice extracellulaire sur la migration des cellules souches de glioblastome : un modèle tridimensionnel de culture et une nouvelle stratégie thérapeutique. Médecine humaine et pathologie. Université Montpellier, 2017. Français. ⟨NNT : 2017MONTT006⟩. ⟨tel-02118022⟩

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