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Rôle de l'intégrine bêta 8 dans le maintien de l'état souche et la radiorésistance des cellules souches de glioblastomes : vers une nouvelle thérapie ciblée

Abstract : Glioblastomas (GB) are invasive, resistant and recurrent brain tumors (median overall survival of 15 months) despite standard treatment including surgical resection, radio- and chemotherapy. This tumor aggressiveness could partly be explained by the presence into the tumor of Glioblastoma-Stem like Cells (GSC), characterized by their ability to self-renew, their higher expression of specific GSC markers, their multipotent aptitude and their high tumorigenic potential. They are strongly involved in tumor resistance and recurrence and their targeting could improve GB treatment. Regarding current literature but also transcriptomic results obtained in our lab, a specific ß8 integrin emerged as a potential selective target in GSC. We then hypothesized that ß8 integrin could be involved in stemness maintenance of GSC. I first demonstrated, during my doctoral thesis, that ß8 is overexpressed in primocultures of GSC isolated from patients resections and also in human GB samples. Moreover, I showed that this integrin could be associated with stemness and features unique to these cells, including self-renewal ability, viability, migration and radioresistance. Indeed, the selective inhibition of ß8 in GSC by si/shRNA resulted in vitro in a decrease of neurosphere formation and migration, associated with an increase of differentiation patterns and cell death, this one being potentiated after irradiation. Finally, in vivo, I showed that ß8 inhibition decreased tumorigenesis and increased mice survival. In conclusion, my doctoral results allow to identify ß8 integrin as a membrane protein essential for stemness maintenance of GSC but mostly as a new potential radiosensitizing therapeutic target for GB.
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Laure Malric. Rôle de l'intégrine bêta 8 dans le maintien de l'état souche et la radiorésistance des cellules souches de glioblastomes : vers une nouvelle thérapie ciblée. Médecine humaine et pathologie. Université Paul Sabatier - Toulouse III, 2018. Français. ⟨NNT : 2018TOU30109⟩. ⟨tel-02407561⟩

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