Inhibiting Integrin Beta8 to Differentiate and Radiosensitize Glioblastoma-initiating Cells
Menée à partir d'échantillons tumoraux prélevés sur 14 patients atteints d'un glioblastome puis menée in vitro et à l'aide d'une xénogreffe orthotopique, cette étude française met en évidence l'intérêt de cibler l'intégrine bêta-8 pour favoriser la différenciation des cellules souches cancéreuses et les sensibiliser aux rayonnements ionisants
Glioblastomas (GBs) are malignant brain tumors with poor prognosis despite treatment with surgery and radio/chemotherapy. These tumors are defined by an important cellular heterogeneity and notably contain a subpopulation of Glioblastoma-initiating cells (GICs), which contribute to tumor aggressiveness, resistance and recurrence. Some integrins are specifically expressed by GICs and could be actionable targets to improve glioblastoma treatment. Here, integrin β8 (ITGB8) was identified as a potential selective target in this highly tumorigenic GIC subpopulation. Using several patient-derived primocultures it was demonstrated that integrin β8 is overexpressed in GICs compared to their differentiated progeny. Furthermore, integrin β8 is also overexpressed in glioblastoma and its overexpression is correlated with poor prognosis and with the expression of several other classic stem cell markers. Moreover, inhibiting integrin β8 diminished several main GIC characteristics and features, including self-renewal ability, stemness, migration potential and tumor formation capacity. Blockade of integrin β8 integrin significantly impaired GIC cell viability via apoptosis induction. Finally, the combination of radiotherapy and integrin β8 targeting radiosensitized GICs through post-mitotic cell death. Implications: This study identifies integrin β8 as a new selective marker for glioblastoma-initiating cells and as a promising therapeutic target in combination with chemo-radiotherapy for the treatment of highly aggressive brain tumors.