Abstract 5392: Breast cancer cells that preferentially metastasize to lung are more adaptable to varying glucose levels compared to those that metastasize to the liver

Abstract Metastasis is the primary cause of breast cancer-related deaths. We investigated the metabolic adaptations of glucose, a major energy substrate, in breast cancer cells that metastasize to lung versus liver to determine the metabolic adaptations that may support site-specific metastasis. Utilizing a breast cancer model that preferentially metastasizes to the lung (metM-WntLung cells; MLg) or liver (metM-WntLiver cells; MLr), we measured 14C-glucose uptake, 13C6-glucose flux into metabolic pathways, and viability under varying glucose concentrations. Results show that in 5 mM glucose (normal), MLg is more glycolytic with greater flux of 13C6-glucose-derived carbons into the glycolytic intermediates pyruvate and lactate in comparison to MLr. In contrast, MLr showed higher levels of 13C6-glucose-derived carbons in the tricarboxylic acid cycle metabolites including oxaloacetate and malate indicative of higher oxidative phosphorylation and higher pyruvate carboxylase (PC) activity. Interestingly, high glucose (25 mM) exposure reduced viability of MLr by 39%, suggesting MLg’s adaptability to varying glucose levels. Although glucose uptake similarly increased in all cell lines under high glucose, flux results showed greater oxidative phosphorylation and increased PC activity in MLg, while MLr shifted to a more glycolytic phenotype. These results were consistent with improved oxidative stress protection in high glucose in MLg, but not MLr. Further, MLg deprived of glucose were more viable (9%) compared to MLr, suggesting a potential alternate use of other substrates to overcome glucose deprivation. Inhibiting the rate-limiting enzyme for gluconeogenesis, phosphoenolpyruvate carboxykinase, reduced viability of MLg by 9% compared to MLr. Further, inhibiting the catabolism of glutamine, a gluconeogenic substrate, reduced viability of MLg by 13% compared to MLr, suggesting that MLg utilizes the contribution of glutamine and gluconeogenesis in conditions of low glucose. Overall, breast cancer cells with preferential metastasis to lung are more adaptable to varying glucose concentrations than breast cancer cells with preferential metastasis to liver by shifting metabolism from glycolysis to oxidative phosphorylation under high glucose conditions and utilizing glutamine and gluconeogenesis under low glucose conditions. Citation Format: Marjorie Anne A. Layosa, Mike Wendt, Stephen Hursting, Dorothy Teegarden. Breast cancer cells that preferentially metastasize to lung are more adaptable to varying glucose levels compared to those that metastasize to the liver [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 5392.