Journal article
Hypoxia-mediated repression of pyruvate carboxylase drives immunosuppression
Breast cancer research : BCR, Vol.26(1), 96
06/07/2024
DOI: 10.1186/s13058-024-01854-1
PMCID: PMC11161980
PMID: 38849928
Abstract
Background Metabolic 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.
Details
- Title: Subtitle
- Hypoxia-mediated repression of pyruvate carboxylase drives immunosuppression
- Creators
- Michael Coleman - University of North Carolina at Chapel HillEylem CotulAlexander Pfeil - University of North Carolina at Chapel HillEmily Devericks - University of North Carolina at Chapel HillMuhammad Safdar - Purdue University West LafayetteMarvis Monteiro - Purdue University West LafayetteHao Chen - Purdue University West LafayetteAlyssa Ho - University of North Carolina at Chapel HillNumair Attaar - University of North Carolina at Chapel HillHannah Malian - University of North Carolina at Chapel HillViolet Kiesel - University of North Carolina at Chapel HillAlexis Ramos - University of IowaMatthew Smith - University of IowaHeena Panchal - University of IowaAdam Mailloux - University of IowaDorothy Teegarden - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- Breast cancer research : BCR, Vol.26(1), 96
- Publisher
- BioMed Central
- DOI
- 10.1186/s13058-024-01854-1
- PMID
- 38849928
- PMCID
- PMC11161980
- ISSN
- 1465-5411
- eISSN
- 1465-542X
- Language
- English
- Date published
- 06/07/2024
- Academic Unit
- Microbiology and Immunology; Internal Medicine
- Record Identifier
- 9984643649102771
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