Glioblastoma (GBM) is the most frequent primary tumor of the central nervous system with a median survival of 16 months, despite the combination of radio- and chemotherapy following surgical resection. This poor prognosis is the consequence of systematic relapses occurring despite state-of-the art therapeutic modalities. It is clearly demonstrated now that GBM are heterogeneous in a sense that only a restricted population of tumor cells, called GBM-Initiating Cells (GIC), are able to give rise to a tumor. Using an in vivo model of brain cancer invasion (xenograft of human GBM cells in the right striatum of nude mice), we demonstrated that some GBM cells migrate specifically to the subventricular zone (SVZ), one of the two neurogenic regions in theadult brain. Those SVZ-nested GBM cells exhibit stemness features and could thus be considered as GIC. This specific invasion of the SVZ by GBM cells is driven by SVZ secretion of CXCL12 acting via CXCR4 receptors expressed by tumor cells. Moreover, SVZ-produced CXCL12 induces GBM radioresistance. Besides CXCR4, CXCL12 can also interact with ACKR3/CXCR7 receptor whose affinity for CXCL12 is ten times higher. ACKR3 has been initially proposed to be a decoy receptor but recently, it was demonstrated thatthis receptor is able to induce signalization and is also able to heterodimerize with CXCR4. In this project, we propose to investigate the possible role of ACKR3 in GBM cells migration in the SVZ. More concretely, we will1) finely analyze the expression of both receptors by GBM cells in collected tumors available at the biobank, in primary GBM cells seeded in cultures in our laboratory and in GBM cells grafted in immunodeficient mice; 2) we will modify the expression of ACKR3 in SVZ cells in order to analyze the consequences of the GBM cells migration to SVZ overexpressing ACKR3 or invalidated for ACKR3 expression; 3) we will unravel the signalization induced by ACKR3 in GBM cells.
|Effective start/end date||1/07/21 → 30/11/23|
- FNRS - Fonds National de la Recherche Scientifique: €250,000.00
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.