STEM-12. TRANSLATION UPREGULATION OF HOXC10 MAINTAINS GLIOMA STEM CELLS IN THE HYPOXIC NICHE

Abstract Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults, with a median survival of only 15 months. Glioma stem cells (GSCs), key drivers of chemotherapeutic resistance and recurrence, persist in both hypoxic and normoxic tumor regions, maintaining stemness and self-renewal. However, mechanisms supporting GSC maintenance in hypoxic conditions remain poorly understood, particularly at the level of translation, as most prior studies have focused on transcriptional changes. We found that GSCs exhibit higher global levels of translation than differentiated glioma cells, supporting the rationale for investigating translation control in these cells. Here, we employed ribosome profiling (RIBO-seq) and RNA sequencing (RNA-seq) in patient-derived GSC lines under hypoxic and normoxic conditions to systematically evaluate gene regulation at both transcription and translation levels. Genes were clustered based on regulatory responses, and a translation efficiency score was assigned to each gene. We identified 123 genes with increased translation efficiency in hypoxic GSCs, independent of changes in mRNA abundance, highlighting the importance of translation control. The top candidate, the homeobox transcription factor HOXC10, was markedly upregulated at the level of translation in hypoxia. shRNA-mediated knockdown of HOXC10 reduced GSC viability, diminished stemness, and decreased tumor-sphere formation in vitro under both oxygen conditions, with more pronounced effects in hypoxia. Conversely, HOXC10 overexpression improved GSC viability in hypoxia. In orthotopic xenograft mouse models, HOXC10 depletion significantly increased median survival. In the Human Protein Atlas, HOXC10 protein expression is elevated in high-grade glioma compared to low-grade glioma, and in the CPTAC GBM dataset, low HOXC10 protein levels were associated with longer patient survival. Our findings reveal that HOXC10 translation is upregulated in hypoxic GSCs and identify HOXC10 as a promising, translation-regulated therapeutic target for GBM. Our ongoing studies aim to elucidate the downstream mechanisms by which HOXC10 confers a survival advantage to GSCs.