Abstract 4154: Cancer cells exhibit novel metabolic vulnerabilities when exposed to low lipid environments

Abstract Cancer cell metabolism is significantly influenced by microenvironmental factors such as nutrient availability, which can vary across different tissues and introduce exploitable therapeutic vulnerabilities. Notably, lipid availability is particularly low in the brain compared to other tissues. To identify metabolic vulnerabilities of cells in lipid-poor environments, we performed a CRISPR/Cas9 screen of metabolic synthesis genes in human cancer cells cultured in lipid-rich versus lipid-poor media. Through this screen, we observed a novel metabolic dependency in the cells when grown in lipid-depleted conditions. We verified this differential dependency by knockout (KO) of this target gene, which resulted in slower cell proliferation in lipid-depleted media. Additionally, wild-type cells displayed heightened sensitivity to inhibitors of other proteins in the pathway in lipid-depleted conditions, thereby phenocopying the KO. Polar metabolomics analyses by LC-MS revealed depletion of several nucleotide species in the KO cells cultured in lipid-depleted conditions, and supplementation with purine nucleotides rescued the proliferation of KO cells cultured in lipid-depleted media. We hypothesized that this nucleotide depletion could in turn result in nucleotide imbalance and DNA damage, and Western Blot analyses confirmed elevated DNA damage levels in the KO cells in lipid-depleted media. Our model is that in low-lipid environments, the KO redirects metabolic resources toward lipid synthesis, causing nucleotide imbalance, DNA damage, and cell death. Overall, our findings indicate that cancer cells exhibit novel metabolic vulnerabilities when exposed to lipid-depleted environments, which could be leveraged for treating tumors growing in lipid-poor organs such as the brain. Citation Format: Diya L. Ramesh, Keene L. Abbott, Raphael Ferreira, Matthew G. Vander Heiden. Cancer cells exhibit novel metabolic vulnerabilities when exposed to low lipid environments [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 4154.