PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer
Open accessAbstract
Metabolic reprogramming is a hallmark of cellular transformation, yet little is known about metabolic changes that accompany tumor metastasis. Here we show that primary breast cancer cells display extensive metabolic heterogeneity and engage distinct metabolic programs depending on their site of metastasis. Liver-metastatic breast cancer cells exhibit a unique metabolic program compared to bone- or lung-metastatic cells, characterized by increased conversion of glucose-derived pyruvate into lactate and a concomitant reduction in mitochondrial metabolism. Liver-metastatic cells displayed increased HIF-1α activity and expression of the HIF-1α target Pyruvate dehydrogenase kinase-1 (PDK1). Silencing HIF-1α reversed the glycolytic phenotype of liver-metastatic cells, while PDK1 was specifically required for metabolic adaptation to nutrient limitation and hypoxia. Finally, we demonstrate that PDK1 is required for efficient liver metastasis, and its expression is elevated in liver metastases from breast cancer patients. Our data implicate PDK1 as a key regulator of metabolism and metastatic potential in breast cancer.
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PDK1 expression was elevated in breast cancer liver metastases compared to primary tumor specimens.
“Notably, PDK1 expression was elevated in breast cancer liver metastases compared to primary tumor specimens, further supporting the notion that PDK1 expression is particularly important for the growth and survival of breast cancer cells within the liver microenvironment.”
From Hypoxic control of metastasis (2016) · cites this paper as [111]
Breast metastases to the liver are highly dependent on glycolysis for survival in comparison to bone and lung metastases.
“Consistent with the concept that hepatic hypoxia and the associated glycolytic phenotype in periportal regions of the liver provide a barrier for metastatic colonization, Dupuy and colleagues observed that breast metastases to the liver are highly dependent on glycolysis for survival in comparison to bone and lung metastases (111).”
From Hypoxic control of metastasis (2016) · cites this paper as [111]
The metabolic reprogramming of liver-metastatic breast cancer cells was largely dependent on the HIF-1 target gene PDK1.
“The metabolic reprogramming of liver-metastatic breast cancer cells was largely dependent on the HIF-1 target gene pyruvate dehydrogenase kinase (PDK1).”
From Hypoxic control of metastasis (2016) · cites this paper as [111]
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- Authors
- Dupuy, F., Tabariès, S., Andrzejewski, S., Dong, Z., Blagih, J., Annis, M. G., Omeroglu, A., Gao, D., Leung, S., Amir, E., Clemons, M., Aguilar-Mahecha, A., Basik, M., Vincent, E. E., St.-Pierre, J., Jones, R. G., & Siegel, P. M.
- Affiliations
- McGill University (CA)
- University of British Columbia (CA)
- University of Toronto (CA)
- Ottawa Hospital (CA)
- Jewish General Hospital (CA)
- Corresponding author
- Jones, Russell G.
- Siegel, Peter M.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 22
- Issue
- 4
- Pages
- 577-589
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W1929533080
- Cited by
- 558
- References
- 41
- Citations by year
- 2026: 24 · 2025: 48 · 2024: 47 · 2023: 64 · 2022: 62 · 2021: 83 · 2020: 58 · 2019: 57 · 2018: 44 · 2017: 40 · 2016: 28 · 2015: 3
- FWCI
- 12.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-93 799, 136907_1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- PDK1, pyruvate dehydrogenase kinase 1, metabolic reprogramming, breast cancer metastasis, liver metastasis, HIF-1α, glycolysis, mitochondrial metabolism, hypoxia, nutrient limitation, tumor metabolic heterogeneity, metastatic potential
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Animals, Breast Neoplasms, Carbon Isotopes, Female, Glutamine, Glycolysis, Humans, Liver Neoplasms, Gas Chromatography-Mass Spectrometry, Mice, Inbred BALB C, Oxidative Phosphorylation, Cell Hypoxia, Protein Serine-Threonine Kinases, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Metabolome, Metabolic Engineering
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