EPCO-46. INTEGRATED STRESS RESPONSE ACTIVATION AND EPIGENETIC REGULATION IN CENTRAL NERVOUS SYSTEM (CNS) TUMORS REVEALS A TUMOR SURVIVAL MECHANISM

Abstract Central nervous system (CNS) tumors originate from neuroectodermal cells and cause a significant burden of neurological and systemic disease in humans. CNS tumors exhibit diverse biological behaviors, ranging from benign, slow-growing masses to highly aggressive, infiltrative malignancies. We found activation of integrated stress response (ISR) in tumor cells. ISR is the final common pathway activated in response to a range of cellular stressors. ISR activation suppresses global protein translation except ATF4, leading to apoptosis in normal cells. Tumors can evade ISR activation to support proliferation, making ISR targetable. The relevance of ISR activation in the context of CNS tumors is unknown. ISR activation was analyzed with single cell transcriptomes (scRNAseq) and single cell ATAC seq (scATACseq) of pituitary adenomas (PA), schwannomas (SCH), and ependymomas (EPN) tumors from our patients. Analysis was supplemented with publicly available datasets including scRNAseq from medulloblastomas (MB) and meningiomas (MG), and corresponding human normal tissue datasets. ISR activity scores were significantly (p<0.05) higher in PA, EPN and MG tumor cells compared to their normal counterparts. Global functional enrichment analysis between tumor and normal cells revealed upregulation of translation, protein folding, and ER stress-related pathways. ATF4 target genes ATF6, and XBP1 were upregulated in tumor cells. These genes mediate ER stress resolution and drive the expression of HSPA5 (BiP), a molecular chaperone. HSPA5 itself was upregulated in tumor cells as well. scATACseq revealed increased promoter accesibility in several ISR-regulated genes including HSPA5, XBP1, and DDIT3 suggesting broad epigenetic reprogramming that allows ISR escape. Our findings suggests that ISR activation in some CNS tumors (PA, EPN, and MG) may play a critical role in tumor adaptation by enhancing protein homeostasis and stress resilience. These findings highlight the ISR escape as a tumor adaptation mechanism and potential therapeutic target in CNS tumors like PA, EPN, and MG.