Journal article
Adaptability of lung and liver metastatic breast cancer cells to glucose
Cancer cell international, Vol.25(1), 374
10/24/2025
DOI: 10.1186/s12935-025-04006-3
PMCID: PMC12676851
PMID: 41345939
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-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.
Details
- Title: Subtitle
- Adaptability of lung and liver metastatic breast cancer cells to glucose
- Creators
- Marjorie Anne Layosa - Purdue University Institute for Cancer ResearchMadeline P. Sheeley - Purdue University West LafayetteAlekya Raghavan - Purdue University West LafayetteChaylen Andolino - Purdue University Institute for Cancer ResearchMichael K. Wendt - University of IowaStephen D. Hursting - University of North Carolina at Chapel HillDorothy Teegarden - Purdue University Institute for Cancer Research
- Resource Type
- Journal article
- Publication Details
- Cancer cell international, Vol.25(1), 374
- DOI
- 10.1186/s12935-025-04006-3
- PMID
- 41345939
- PMCID
- PMC12676851
- NLM abbreviation
- Cancer Cell Int
- ISSN
- 1475-2867
- eISSN
- 1475-2867
- Publisher
- BioMed Central
- Grant note
- Purdue Women’s Global Health Institute P30CA023168; P30CA023168; P30CA023168 / Purdue University Institute for Cancer Research R01CA232589 and R01CA271597; R01CA232589 and R01CA271597; R01CA232589 and R01CA271597; R01CA232589 and R01CA271597; R01CA232589 and R01CA271597; R01CA232589 and R01CA271597; R01CA232589 and R01CA271597 / National Institute of Health NIH/NCRR (#TR000006); NIH/NCRR (#TR000006); NIH/NCRR (#TR000006); NIH/NCRR (#TR000006); NIH/NCRR (#TR000006) / Indiana Clinical Translational Science Institute
- Language
- English
- Date published
- 10/24/2025
- Academic Unit
- Holden Comprehensive Cancer Center; Internal Medicine
- Record Identifier
- 9985090731302771
Metrics
4 Record Views