Glioblastoma is the most frequent and aggressive primary brain tumour inadults and is still essentially incurable. The chemokine receptor CXCR3 isimplicated in many cancers, including glioblastoma, and controls tumourgrowth, migration and invasion. CXCR3 exists as two major splice variants,CXCR3A and CXCR3B, differing only by the presence of an N-terminal 52-amino acid extension in the isoform B. In numerous tumoral tissues and celllines these two isoforms were shown to have opposite effects on cancerdevelopment, with CXCR3A inducing cell proliferation and invasivephenotype and CXCR3B having pro-apoptotic and anti-proliferative effects.However, so far the molecular mechanisms behind these opposite activitiesremain poorly understood and under-investigated. The aim of this project istherefore to decipher the molecular mechanisms underlying the opposingactivities of the two CXCR3 isoforms. Our efforts will first be directedtowards four convergent approaches: (I) editing the genome ofglioblastoma-derived cells to express only one of the two isoforms andusing these cells for (II) unravelling specific intracellular signalling pathwaysactivated by each isoform, (III) assessing the cellular localisation andtrafficking properties of the two isoforms in the context of cancer biology and(IV) examining their impact on cell proliferation, migration and survival invitro and in vivo. These questions will be addressed by applying differentmolecular, cellular and pharmacological approaches. The results will bethen further confirmed using patient-derived tumour samples and/or patient-derived orthotopic xenograft (PDOX) models. The ultimate goal of thepresent project will be to provide the molecular basis to design novel biasedallosteric modulators, which by binding to CXCR3, induce receptor activityswitch, triggering exclusively the anti-tumoral signalling pathways ofCXCR3B.
|Effective start/end date||15/05/20 → 14/10/24|
- FNRS - Fonds National de la Recherche Scientifique: €111,954.00
- FNRS - Fonds National de la Recherche Scientifique: €95,954.00
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