Hypoxia-driven heterogeneous expression of α5 integrin in glioblastoma stem cells is linked to HIF-2α
Résumé
Despite numerous molecular targeted therapies tested in glioblastoma (GBM), no significant progress in patient survival has been achieved in the last 20 years in the overall population of GBM patients. Therapy resistance is associated with target expression heterogeneity and plasticity between tumors and in tumor niches. We focused on a5 integrin implicated in aggressive GBM in preclinical and clinical samples. To address the characteristics of a5 integrin heterogeneity we started with patient data indicating that elevated levels of its mRNA are related to hypoxia pathways. We turned on glioma stem cells which are considered at the apex of tumor formation and recurrence but also as they localize in hypoxic niches. We demonstrated that a5 integrin expression is stem cell line dependent and is modulated positively by hypoxia in vitro. Importantly, heterogeneity of expression is conserved in in vivo stem cell-derived mice xenografts. In hypoxic niches, HIF-2α is preferentially implicated in a5 integrin expression which confers migratory capacity to GBM stem cells. Hence combining HIF-2α and a5 integrin inhibitors resulted in proliferation and migration impairment of a5 integrin expressing cells. Stabilization of HIF-2α is however not sufficient to control integrin a5 expression. Our results show that AHR (aryl hydrocarbon receptor) and HIF-2α expressions are inversely correlated and to a5 integrin expression suggesting a functional competition between both transcription factors. Collectively, data confirm the high heterogeneity of a GBM therapeutic target, its induction in hypoxic niches by HIF-2α and suggest a new way to attack molecularly defined GBM stem cells.
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