CNSC-56. HUMAN ENDOGENOUS RETROVIRUS K ENV ACTIVATES CD98HC/EGFR SIGNALING TO PROMOTE GLIOBLASTOMA PROGRESSION

Abstract Human endogenous retrovirus-K (HERV-K), particularly the HML-2 subtype, is the most recently integrated human provirus and remains transcriptionally active in several cancers, including glioblastoma (GBM). Although its function in GBM has been poorly defined, we previously identified HERV-K envelope (Env) as a critical component of the GBM stem cell niche. Our recent studies uncovered a novel oncogenic signaling axis wherein HERV-K Env promotes GBM progression through CD98hc-mediated activation of EGFR signaling. Using patient-derived GBM cell lines, we demonstrate that HERV-K Env overexpression significantly enhances tumor proliferation (xCELLigence real-time cell analysis, p<0.01), whereas knockdown of HERV-K Env or CD98hc suppresses tumor growth and spheroid formation (p<0.001). Protein interaction studies, co-immunoprecipitation and immunofluorescence colocalization, revealed a direct association between HERV-K Env and CD98hc, leading to EGFR phosphorylation at tyrosine residues Y845 and Y992 and activation of FAK, Src, MAPK, and Akt pathways, events linked to mitochondrial dysfunction and enhanced malignancy. Spatial transcriptomic analysis of patient GBM samples (n=11) revealed that regions with elevated HERV-K (ERVK3-1 and ERVK8) expression also exhibited increased EGFR and stemness markers, particularly within Olig2-positive populations. In vivo, HERV-K Env knockdown significantly prolonged survival in orthotopic murine GBM models (median OS: 24.0 vs. 18.0 days, p = 0.0101, n=10). To translate these findings, we developed antisense oligonucleotides (ASOs) targeting HERV-K Env, which significantly reduced GBM cell viability (p<0.001) without affecting human astrocytes, highlighting specificity. Profiling of iPSC-derived cerebral organoids revealed high co-expression of HERV-K Env and key stemness regulators OCT4 and SOX2 during early neurodevelopmental stages. Ongoing studies are reactivating HERV-K Env in astrocytes and organoids to study its role in neural identity and oncogenic potential. Together, our findings define the HERV-K Env/CD98hc/EGFR axis as a therapeutic vulnerability in GBM and support the development of precision strategies targeting treatment-resistant tumor stem cells.