TMIC-25. MICROGLIA IN THE GLIOBLASTOMA MICROENVIRONMENT SECRETE ACETYLATED AMINO ACIDS WHICH ASSIST IN THE REPAIR OF RADIATION INDUCED DNA DAMAGE

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 26; no. Supplement_8; p. viii303
• Main Authors: Palavalasa, Sravya, Freeman, Jack, Singer, Ava, Gokul, Aditri, Baker, Emily, Scott, Andrew, Wilder-Romans, Kari, Shankar, Sunita, Ravikumar, Visweswaran, Andren, Anthony, Wong, Harrison, Sajjakulnikit, Peter, Bhaduri, Sagnik, Zhou, Weihua, Lyssiotis, Costas, Rao, Arvind, Al-holou, Wajd, Wahl, Daniel
• Format: Journal Article
• Language: English
• Published: 11-11-2024
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noae165.1203

Rapid repair of DNA damage mediates genotoxic therapy resistance and poor prognosis in glioblastoma (GBM). The GBM tumor microenvironment (TME) is heterogenous, and we hypothesized that non-malignant cells support the repair of DNA damage in glioblastoma cells. Consistent with this hypothesis, we found that GBM tumors grown intracranially in mice had rapid DNA repair and were resistant to radiation compared to tumors of identical genotype grown extracranially in mouse flanks. Further interrogation of irradiated intracranial tumors using gamma-H2AX immunofluorescence revealed spatial heterogeneity in DNA damage repair, with spatially separate regions of rapid and slow gamma-H2AX resolution. Paired spatial transcriptomic analysis and gamma-H2AX immunofluorescence showed that tumor regions with rapid DNA repair were rich in microglia. Having nominated microglia from these results, we cocultured GBM cells and microglia in direct contact as well as in transwell coculture. We found that GBM cells cocultured with microglia repair DNA damage faster in a contact-independent manner. We then assessed the supernatant metabolome of microglia and GBM monocultures and cocultures and found that acetylated amino acids are secreted by microglia and consumed by GBM cells. Supplementation with acetylated amino acids promotes radiation resistance by speeding the repair of radiation-induced DNA damage. Mechanistically, acetylated amino acid supplementation allows glioma cells to re-route glucose utilization away from the TCA cycle and towards nucleotide synthesis. Hence, we show that microglia in the GBM microenvironment assist GBM cells to repair radiation induced DNA damage by secreting acetylated amino acids which are consumed by GBM cells and used to fuel the TCA cycle allowing utilization of glucose for nucleotide synthesis, thereby making the GBM cells resistant to radiation therapy.