Project Grant R03NS142535

DECIPHERING THE ROLE OF THE NOVEL LONG NON-CODING RNA LINC01896 IN GLIOBLASTOMA MULTIFORME - PROJECT SUMMARY GLIOBLASTOMA MULTIFORME (GBM) IS THE MOST AGGRESSIVE AND COMMON PRIMARY BRAIN TUMOR, POSING SIGNIFICANT CLINICAL CHALLENGES DESPITE MULTIMODAL TREATMENTS LIKE SURGICAL RESECTION, CHEMOTHERAPY, AND RADIATION. THE PROGNOSIS FOR GBM PATIENTS REMAINS POOR, PRIMARILY DUE TO ITS INEVITABLE RECURRENCE AND RESISTANCE TO STANDARD THERAPIES. THEREFORE, IDENTIFYING NOVEL MOLECULAR DRIVERS OF GBM PROGRESSION IS ESSENTIAL FOR DEVELOPING MORE EFFECTIVE TREATMENTS. OVER THE PAST DECADE, THE ISOLATION OF GLIOBLASTOMA STEM CELLS (GSCS) HAS PROVIDED CRUCIAL INSIGHTS INTO TUMOR INITIATION, MAINTENANCE, AND RECURRENCE, POSITIONING THEM AS A MAJOR THERAPEUTIC TARGET. CONCURRENTLY, ADVANCES IN GENOMIC RESEARCH HAVE REVEALED A VAST LANDSCAPE OF LONG NONCODING RNAS (LNCRNAS), OFFERING NEW OPPORTUNITIES TO INFLUENCE GENE REGULATION AND CANCER BIOLOGY. ALTHOUGH TENS OF THOUSANDS OF LNCRNAS HAVE BEEN DISCOVERED, ONLY A SMALL FRACTION HAVE BEEN FUNCTIONALLY CHARACTERIZED. EMERGING EVIDENCE SUGGESTS THAT LNCRNAS EXHIBIT CELL-TYPE-SPECIFIC EXPRESSION, DISTINCT SUBCELLULAR LOCALIZATION, AND CRITICAL ROLES IN KEY ONCOGENIC PROCESSES, INCLUDING PROLIFERATION, INVASION, AND THERAPY RESISTANCE. THESE PROPERTIES HIGHLIGHT THEIR POTENTIAL AS BOTH BIOMARKERS AND THERAPEUTIC TARGETS IN GBM. IN THIS STUDY, WE PROPOSE TO CHARACTERIZE THE NUCLEAR-RETAINED ONCOGENIC LNCRNA, LINC01896, WHICH IS SIGNIFICANTLY UPREGULATED IN GSCS. OUR PRELIMINARY DATA SHOW THAT DEPLETION OF LINC01896 IMPAIRS GSC PROLIFERATION AND STEMNESS, EMPHASIZING ITS CRITICAL ROLE IN GSC MAINTENANCE. FURTHERMORE, HIGHER LEVEL OF LINC01896 CORRELATES WITH POOR OVERALL AND DISEASE-FREE SURVIVAL IN GBM PATIENTS, SUGGESTING ITS POTENTIAL AS BOTH A PROGNOSTIC BIOMARKER AND A THERAPEUTIC TARGET. WE WILL INVESTIGATE HOW LINC01896 REGULATES GLOBAL GENE EXPRESSION IN GSCS AND IDENTIFY THE MOLECULAR PATHWAYS DRIVING GSC PROLIFERATION AND STEMNESS. ADDITIONALLY, WE WILL EXAMINE THE FUNCTIONAL IMPACT OF LINC01896 KNOCKDOWN IN GSCS USING ANTISENSE OLIGONUCLEOTIDES (ASOS) AND EVALUATE THESE EFFECTS IN PRECLINICAL 3D CEREBRAL ORGANOID MODEL, WHICH MIMIC THE HUMAN BRAIN'S CELLULAR COMPLEXITY AND TUMOR MICROENVIRONMENT. FURTHERMORE, WE WILL MAP THE TRANSCRIPTOMIC LANDSCAPE OF GSCS AND THEIR TUMOR MICROENVIRONMENT USING SINGLE-CELL RNA SEQUENCING. TOGETHER, THESE STUDIES AIM TO ELUCIDATE THE REGULATORY ROLE OF LINC01896 IN GSC BIOLOGY AND PAVE THE WAY FOR THE DEVELOPMENT OF INNOVATIVE LNCRNA-BASED THERAPEUTIC STRATEGIES FOR GBM PATIENTS.