LGG-04. CLINICALLY RELEVANT MODELING OF FUSION-DRIVEN PEDIATRIC LOW GRADE GLIOMAS USING DROSOPHILA MELANOGASTER

Abstract Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children, with varying degrees of invasion. Recent whole-genome sequencing has identified a rare gene fusion involving RAF1, RAF isoform. Unlike other fusions, RAF1 fusions resistant to existing inhibitors. Therefore, aside from surgical resection adjuvant chemotherapy and radiation therapy, there few targeted therapeutic alternatives for RAF1-fusion-driven PLGGs. Despite prevalence challenges this disease presented, our understanding PLGGs was limited by lack genetic models. We ultimately picked Drosophila melanogaster as model organism due conservation major signaling pathways between flies humans. Furthermore, connection humans flies, coupled technical advantages associated organism, like short generation cycle its powerful toolbox, makes an ideal study genesis progression With help GAL4/UAS system, we established four fusion-driven PLGG fly models found that glial overexpression QKI-RAF1, pilocytic astrocytomas, induces invasion-like phenotype aberrant migration. This migration defect suppressed repulsive guidance receptors Robo2 or PlexA/B, indicating dysregulation pathways. Immunostaining quantitative analysis revealed expression is downregulated migrating tumor cells which recapitulated mouse astrocytes overexpressing QKI-RAF1 patients fusions. further broaden findings profiling transcriptomes, revealing potential downstream effectors, including G protein-coupled receptor GPR180/CG9304, inhibition suppresses invasion flies. Taken together, present leading discovery Robo2, Plexins, GPR180/CG9304 targets.