ArticleBreast cancer research : BCR2024
Hypoxia-mediated repression of pyruvate carboxylase drives immunosuppression.
Article in Breast cancer research : BCR, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Lactate as a Signaling Molecule in the Tumor Microenvironment: Implications for Cancer Progression.Biochemical genetics · 2026Review
- HIF-1α drives distinct aspects of hypoxia-induced glucose metabolism in intestinal epithelial cells.The Journal of biological chemistry · 2026Article
- Metabolic maintenance of breast cancer cells and metastases through E-cadherin/YAP-dependent pyruvate carboxylase expression.bioRxiv : the preprint server for biology · 2026Article
- Lactate metabolic reprogramming and lactylation modification: molecular mechanisms reshaping the tumor immunosuppressive microenvironment.Cell & bioscience · 2026Review
- Cancer metabolism: bridging tumorigenesis mechanisms to treatment susceptibility.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Tumor microenvironment in breast cancer: cellular crosstalk, pathways, and therapeutic insights.Molecular biology reports · 2025Review
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Authors and funding
18 authors.
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Abstract
backgroundMetabolic plasticity mediates breast cancer survival, growth, and immune evasion during metastasis. However, how tumor cell metabolism is influenced by and feeds back to regulate breast cancer progression are not fully understood. We identify hypoxia-mediated suppression of pyruvate carboxylase (PC), and subsequent induction of lactate production, as a metabolic regulator of immunosuppression.
methodsWe used qPCR, immunoblot, and reporter assays to characterize repression of PC in hypoxic primary tumors. Steady state metabolomics were used to identify changes in metabolite pools upon PC depletion. In vivo tumor growth and metastasis assays were used to evaluate the impact of PC manipulation and pharmacologic inhibition of lactate transporters. Immunohistochemistry, flow cytometry, and global gene expression analyzes of tumor tissue were employed to characterize the impact of PC depletion on tumor immunity.
resultsPC is essential for metastatic colonization of the lungs. In contrast, depletion of PC in tumor cells promotes primary tumor growth. This effect was only observed in immune competent animals, supporting the hypothesis that repression of PC can suppress anti-tumor immunity. Exploring key differences between the pulmonary and mammary environments, we demonstrate that hypoxia potently downregulated PC. In the absence of PC, tumor cells produce more lactate and undergo less oxidative phosphorylation. Inhibition of lactate metabolism was sufficient to restore T cell populations to PC-depleted mammary tumors.
conclusionsWe present a dimorphic role for PC in primary mammary tumors vs. pulmonary metastases. These findings highlight a key contextual role for PC-directed lactate production as a metabolic nexus connecting hypoxia and antitumor immunity.
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