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-WntLung) or liver (metM-WntLiver), 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. Results Under normal glucose conditions, metM-WntLung cells were more glycolytic, exhibiting greater flux of 13C6-glucose-derived carbons into glycolytic intermediates, such as pyruvate and lactate. In contrast, metM-WntLiver 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-WntLiver cell viability, with no effect on metM-WntLung cells, suggesting better adaptability of metM-WntLung cells to glucose excess. This was accompanied by increased PC activity and oxidative phosphorylation in metM-WntLung cells, whereas metM-WntLiver cells shifted to a more glycolytic phenotype. Under glucose deprivation, metM-WntLung cells were more viable than metM-WntLiver cells, suggesting that metM-WntLung cells have better adaptability to glucose deprivation. Inhibiting phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis, reduced metM-WntLung cell viability compared to metM-WntLiver cells. Similarly, inhibiting catabolism of glutamine, a gluconeogenic substrate, decreased metM-WntLung cell viability compared to metM-WntLiver cells, indicating that metM-WntLung cells rely on more on gluconeogenesis and glutamine metabolism under glucose deprivation. Conclusion Our findings reveal that metM-WntLung cells exhibit greater metabolic flexibility to glucose than metM-WntLiver cells by shifting from glycolysis to oxidative phosphorylation under high glucose conditions while utilizing gluconeogenesis and glutamine under glucose deprivation conditions.

Adaptability of lung and liver metastatic breast cancer cells to glucose

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2025年10月24日

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Marjorie Anne Layosa,
Madeline P. Sheeley,
Alekya Raghavan,
Chaylen Andolino,
Michael K. Wendt,
Stephen D. Hursting,
Dorothy Teegarden

摘要

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 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.

Results

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.

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.