Adaptability of lung and liver metastatic breast cancer cells to glucose

Abstract Background Breast cancer is the most common cancer among women, and metastasis is the leading cause of mortality. It is still unknown how breast cancer cells metabolically adapt to successfully metastasize to different organs to survive adverse conditions, including varying nutrient availability. The purpose of this study is to elucidate the metabolic characteristics and glucose adaptation mechanisms of breast cancer cells that preferentially metastasize to the lungs or the liver. Methods Using a Wnt-driven breast cancer model with preferential metastasis to lung (metM-Wnt Lung ) or liver (metM-Wnt Liver ), we measured 14 C-glucose uptake, 13 C 6 -glucose metabolic flux, metabolic enzyme levels, and cell viability under normal (5 mM), high (25 mM), and low (1 or 0 mM) glucose conditions. Results Under normal glucose conditions, metM-Wnt Lung cells were more glycolytic, exhibiting greater flux of 13 C 6 -glucose-derived carbons into glycolytic intermediates, such as pyruvate and lactate. In contrast, metM-Wnt Liver cells favored oxidative phosphorylation, with higher levels of 13 C 6 -glucose-derived carbons in tricarboxylic acid (TCA) cycle metabolites such as oxaloacetate indicative of higher pyruvate carboxylase (PC) activity. Exposure to high glucose reduced metM-Wnt Liver cell viability, with no effect on metM-Wnt Lung cells, suggesting better adaptability of metM-Wnt Lung cells to glucose excess. This was accompanied by increased PC activity and oxidative phosphorylation in metM-Wnt Lung cells, whereas metM-Wnt Liver cells shifted to a more glycolytic phenotype. Under glucose deprivation, metM-Wnt Lung cells were more viable than metM-Wnt Liver cells, suggesting that metM-Wnt Lung cells have better adaptability to glucose deprivation. Inhibiting phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis, reduced metM-Wnt Lung cell viability compared to metM-Wnt Liver cells. Similarly, inhibiting catabolism of glutamine, a gluconeogenic substrate, decreased metM-Wnt Lung cell viability compared to metM-Wnt Liver cells, indicating that metM-Wnt Lung cells rely on more on gluconeogenesis and glutamine metabolism under glucose deprivation. Conclusion Our findings reveal that metM-Wnt Lung cells exhibit greater metabolic flexibility to glucose than metM-Wnt Liver cells by shifting from glycolysis to oxidative phosphorylation under high glucose conditions while utilizing gluconeogenesis and glutamine under glucose deprivation conditions.