ANGI-03. RTN4R-203, A LONG NON-CODING RNA DERIVED FROM THE NEURONAL RTN4/NOGO RECEPTOR GENE, SUPPRESSES MESENCHYMAL TRANSITION VIA ECM REMODELING IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) exhibits dynamic phenotypic plasticity, with the proneural-to-mesenchymal transition (PMT) driving tumor aggressiveness and treatment resistance. However, the molecular mechanisms underlying PMT remain unclear. METHODS Using bulk transcriptomic datasets (TCGA, CGGA) and CRISPR-mediated knockout in LN319 cells, we evaluated the function of RTN4R-203, a transcript of RTN4R predicted to encode a neuronal membrane protein but lacking canonical translational features. Transcriptomic, proteomic, and phenotypic analyses were performed to characterize the impact of RTN4R-203 loss. RESULTS RTN4R expression was reduced in mesenchymal GBM and inversely correlated with PMT gene signatures. RTN4R-203 emerged as the predominant isoform in GBM, and ribosome profiling confirmed its non-coding nature. RTN4R-203 knockout induced a mesenchymal-like phenotype in LN319 cells, with increased motility, spindle-like morphology, and significant upregulation of EGFR, MET, and integrins (ITGA3, ITGA5, ITGB1, ITGB3). Simultaneously, key Proneural markers including PDGFRA and OLIG2 were markedly downregulated, supporting a true PMT shift. Enrichment analysis highlighted ECM remodeling pathways as central mediators, while canonical EMT signaling cascades (TGF-β, WNT, NOTCH) remained inactive. CONCLUSION RTN4R-203 is a previously unrecognized long non-coding RNA that suppresses PMT in GBM by maintaining Proneural identity and repressing ECM-dependent mesenchymal programs. Its loss promotes mesenchymal transition independently of canonical EMT pathways, suggesting a novel axis of tumor plasticity regulation and a potential therapeutic vulnerability in aggressive GBM.