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Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis.
- Source :
-
Redox biology [Redox Biol] 2024 Sep; Vol. 75, pp. 103276. Date of Electronic Publication: 2024 Jul 20. - Publication Year :
- 2024
-
Abstract
- Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations. Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024. Published by Elsevier B.V.)
- Subjects :
- Female
Humans
Animals
Mice
Cell Line, Tumor
Glycolysis
Neoplasm Metastasis
Gene Expression Regulation, Neoplastic
Tumor Microenvironment
Breast Neoplasms pathology
Breast Neoplasms metabolism
Breast Neoplasms genetics
Oxidation-Reduction
Glutathione metabolism
Reactive Oxygen Species metabolism
Liver Neoplasms metabolism
Liver Neoplasms pathology
Liver Neoplasms secondary
Liver Neoplasms genetics
Glutamate-Cysteine Ligase metabolism
Glutamate-Cysteine Ligase genetics
Homeostasis
Subjects
Details
- Language :
- English
- ISSN :
- 2213-2317
- Volume :
- 75
- Database :
- MEDLINE
- Journal :
- Redox biology
- Publication Type :
- Academic Journal
- Accession number :
- 39053265
- Full Text :
- https://doi.org/10.1016/j.redox.2024.103276