Abstract B043: Defective lipid homeostasis drives nuclear envelope disruption and genomic instability during gliomagenesis

Abstract Genomic instability, including chromosomal rearrangements and formation of extrachromosomal DNAs (ecDNAs), is a characteristic of most cancers and is particularly prevalent in glioblastoma (GBM), where it contributes to therapeutic resistance and poor clinical outcomes. However, the metabolic mechanisms underlying ecDNA formation in brain tumors remain poorly understood. By analyzing human glioma data, we identified a strong association between dysregulated lipid metabolism and increased chromosomal structural alterations, with a pronounced enrichment of ecDNA. Fatty acids (FAs) are essential class of lipids, and crucial components of the nuclear membrane (nuclear envelope, NE), which plays a critical role in preserving nuclear architecture and genomic stability. Using a Nestin-CreER T2 ; Qk L/L ; Pten L/L ; Trp53 L/L (QPP) GBM mouse model, we observed abnormal nuclear morphology and ecDNAs accumulation associated with impaired FA desaturation. Supplementation with saturated FAs resulted in NE damage in Nestin-CreER T2 ; Pten L/L ; Trp53 L/L (PP) pre-malignant neural stem cell (PM-NSC), accompanied by increased micronuclei, aberrant mitotic formation and multinucleated giant cells compared with controls. Mechanistically, knockdown of the lipid droplet regulator Seipin in PP PM-NSC phenocopied lipid saturation, inducing extensive NE abnormalities and ecDNA-like structures detectable by scanning electron microscopy. Together, our findings identify defective lipid metabolism, especially dysregulated FA homeostasis as a previously unrecognized driver of NE disruption and genomic instability in gliomagenesis. Our study also reveals a potential metabolic vulnerability in brain cancer that may be therapeutically exploited by targeting lipid homeostasis. Citation Format: Yinglu Guan, Kaylene J. Lu, Ece Kilinc, Takashi Shingu, Mingxin Li, Jian Hu. Defective lipid homeostasis drives nuclear envelope disruption and genomic instability during gliomagenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B043.