Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent Anaplerosis
Open accessAbstract
Cellular proliferation depends on refilling the tricarboxylic acid (TCA) cycle to support biomass production (anaplerosis). The two major anaplerotic pathways in cells are pyruvate conversion to oxaloacetate via pyruvate carboxylase (PC) and glutamine conversion to α-ketoglutarate. Cancers often show an organ-specific reliance on either pathway. However, it remains unknown whether they adapt their mode of anaplerosis when metastasizing to a distant organ. We measured PC-dependent anaplerosis in breast-cancer-derived lung metastases compared to their primary cancers using in vivo 13 C tracer analysis. We discovered that lung metastases have higher PC-dependent anaplerosis compared to primary breast cancers. Based on in vitro analysis and a mathematical model for the determination of compartment-specific metabolite concentrations, we found that mitochondrial pyruvate concentrations can promote PC-dependent anaplerosis via enzyme kinetics. In conclusion, we show that breast cancer cells proliferating as lung metastases activate PC-dependent anaplerosis in response to the lung microenvironment.
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PC-mediated alternative anaplerosis is important in liver cancers and glioblastoma for maintaining biosynthesis and redox homeostasis.
“This PC-mediated alternative anaplerosis is considered important in specific types of cancers, including liver cancers and glioblastoma, for maintaining biosynthesis and redox homeostasis154–156.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [155]
Many cancers favor PC-mediated anaplerosis.
“Many cancers favor PC-mediated anaplerosis, although the factors that dictate the choice for pyruvate flux between PC and PDC are little studied.27,29,30”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [29]
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“Most proliferating cells, such as cancer cells, exploit the tricarboxylic acid (TCA) cycle for biomass precursor production (Pavlova and Thompson, 2016), a process that is critically Cell This is an open access article under the CC BY-N dependent on sufficient anaplerosis.”
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- Authors
- Christen, S., Lorendeau, D., Schmieder, R., Broekaert, D., Metzger, K., Veys, K., Elia, I., Buescher, J. M., Orth, M. F., Davidson, S. M., Grünewald, T. G. P., De Bock, K., & Fendt, S.-M.
- Affiliations
- KU Leuven (BE)
- Pathologisches Institut (DE)
- Koch Institute for Integrative Cancer Research At MIT (US)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Corresponding author
- Fendt, Sarah-Maria
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 17
- Issue
- 3
- Pages
- 837-848
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2530547043
- Cited by
- 258
- References
- 38
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 30 · 2023: 18 · 2022: 32 · 2021: 41 · 2020: 26 · 2019: 26 · 2018: 26 · 2017: 18 · 2016: 2
- FWCI
- 9.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Lirias (submittedVersion, cc-by-nc-nd)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- ETH Zürich Research Collection
- Funders
- Concern Foundation
- Daimler und Benz Stiftung
- Fonds Wetenschappelijk Onderzoek
- Deutsche Krebshilfe (DKH-111886, DKH-70112257, 111886, 70112257)
- University of California, San Diego
- 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
- breast cancer, lung metastasis, pyruvate carboxylase, anaplerosis, TCA cycle, oxaloacetate, tumor microenvironment, cancer metabolism
- MeSH terms
- Acetyl Coenzyme A, Adenosine Diphosphate, Adenosine Triphosphate, Breast Neoplasms, Carbon Isotopes, Cell Compartmentation, Citric Acid Cycle, Cytosol, Female, Humans, Isotope Labeling, Lung Neoplasms, Mitochondria, Pyruvate Carboxylase, Pyruvic Acid, Cell Line, Tumor, Tumor Microenvironment
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