Adaptability of lung and liver metastatic breast cancer cells to glucose

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.

Using a Wnt-driven breast cancer model with preferential metastasis to lung (metM-Wnt^Lung) or liver (metM-Wnt^Liver), we measured ¹⁴C-glucose uptake, ¹³C₆-glucose metabolic flux, metabolic enzyme levels, and cell viability under normal (5 mM), high (25 mM), and low (1 or 0 mM) glucose conditions.

Under normal glucose conditions, metM-Wnt^Lung cells were more glycolytic, exhibiting greater flux of ¹³C₆-glucose-derived carbons into glycolytic intermediates, such as pyruvate and lactate. In contrast, metM-Wnt^Liver cells favored oxidative phosphorylation, with higher levels of ¹³C₆-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.

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.