Abstract 6659: Defective lipid homeostasis induced by QKI loss is a mutator on gliomagenesis

Abstract Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is also one of the deadliest and most treatment-resistant cancers with more than 14, 490 cases diagnosed in the United States in 2023. Tumorigenesis is a multistep process that starts with the occurrence of an oncogenic mutation in a single somatic cell. Despite extensive information about mutators for many cancers, the specific mutator driving GBM development remains unclear. Interrogating human glioma genomic and transcriptomic data revealed that defective lipid metabolism is associated with increased structural variants, particularly extrachromosomal DNA (ecDNA) formation. Quaking (QKI) is frequently mutated or deleted in human GBMs. Mechanistically, QKI acts as an RNA binding protein to regulate pre-mRNA stability of genes that regulates lipid components of endolysosomes, particularly the unsaturated fatty acids. We identified that QKI modulates neural stem cells and glioma stem cells lipid metabolism and further maintains membrane integrity in mitochondria and nuclear envelope. Deleting Qki on the Nestin-CreERT2; PtenL/L; Trp53L/L background (QPP) strongly enhances gliomagenesis in mice. Using this model, we found Qki loss promoted somatic driver alterations including focal DNA alterations and oncogene amplification on ecDNA, especially Pdgfra/Kit, which as common oncogenes in ecDNA across both human and QPP mouse GBMs. Collectively, this work elucidates novel mechanisms underlying defective lipid homeostasis induced by QKI loss acts as a mutator in promoting gliomagenesis through inducing genomic instability. Our study provides a deeper insight into lipid metabolic dysregulation of GBM and a candidate for diagnosis and therapy. It will also contribute to the development of therapeutic strategies that specifically target QKI-depleted GBM. Citation Format: Yinglu Guan, Takashi Shingu, Kaylene J. Lu, Ece Kilinc, Traver G. Hart, Jianhua Zhang, Yiwen Chen, Betty Y. Kim, Jian Hu. Defective lipid homeostasis induced by QKI loss is a mutator on gliomagenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6659.