ArticleCell death & disease2022
Lactate promotes metastasis of normoxic colorectal cancer stem cells through PGC-1α-mediated oxidative phosphorylation.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 61 citations in OpenAlex.
- LDH isozymes as targets for cancer therapy.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Review
- Cancer stem cell plasticity: mechanisms, immune microenvironment crosstalk, and therapeutic implications.Journal of hematology & oncology · 2026Review
- Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Mitochondrial IκBα fuels cancer progression through metabolic rewiring, endothelial activation, and thrombotic spread.Cell death discovery · 2026Article
- Lactic Acid in Tumour Biology.Metabolites · 2026Review
- BioLM-NET: an interpretable deep learning model combining prior biological knowledge and contextual LLM gene embeddings on multi-omics data to predict disease.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing · 2026Article
- Mitochondrial metabolism in cancer stem cells (CSCs): molecular and diagnostic implications.Frontiers in molecular biosciences · 2026Review
- Lactate metabolism and protein lactylation in colorectal cancer: from metabolic reprogramming to epigenetic regulation.Frontiers in oncology · 2026Review
- Lactate, a Spearhead of Cancer Aggressiveness: Metabolic Reprogramming, Immune Suppression, and Metastatic Progression.Medical principles and practice : international journal of the Kuwait University, Health Science Centre · 2026Review
- Mitochondrial DNA Mutations in Colorectal Cancer Stem Cells: Implications for Tumor Dynamics and Therapeutic Strategies.Current medicinal chemistry · 2026Review
- Bioactive Artificial Cells as Autonomous Metabolic Actuators Enable Bidirectional Communication with Tumor Cells.Journal of the American Chemical Society · 2025Article
- Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer.Nature communications · 2025Article
- Review
- Integrative machine learning-driven prognosis and immunotherapy stratification via lactylation-associated gene in ovarian cancer.NPJ precision oncology · 2025Article
- Lactate and lactylation in cancer: drivers of immune suppression and microenvironmental reprogramming.Experimental hematology & oncology · 2025Review
- Inhibition Profiling ofMolecules (Basel, Switzerland) · 2025Article
- The integration of single-cell and metabolomics reveals the increase of oxidative phosphorylation during the liver metastasis of colorectal cancer.Cancer & metabolism · 2025Article
- 3D Bioprinting and Artificial Intelligence for Tumor Microenvironment Modeling: A Scoping Review of Models, Methods, and Integration Pathways.Molecular pharmaceutics · 2025Article
- Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma.Haematologica · 2025Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Uneven oxygen supply in solid tumors leads to hypoxic and normoxic regions. Hypoxic cells exhibit increased secretion of lactate, which creates an acidic tumor microenvironment (TME). This acidic TME is positively associated with tumor metastasis. Despite the increased metastatic capacity of hypoxic cells, they are located relatively further away from the blood vessels and have limited access to the circulatory system. Studies have shown that cancer stem cells (CSCs) are enriched for tumor metastasis-initiating cells and generally undergo aerobic respiration, which could be enhanced by lactate. We therefore hypothesized that TME-derived lactate may promote the metastasis of normoxic CSCs. In the present study, the abundance of hypoxic and normoxic CSCs was analyzed in primary CRC tumors. It was found that the proportion of normoxic CSCs was positively associated with tumor stage. Using two human CRC cell lines, LoVo and SW480, and a patient-derived xenograft (XhCRC), it was found that treatment with lactate promoted normoxic CSC metastasis. Metabolism analysis indicated that, upon treatment with lactate, oxidative phosphorylation (OXPHOS) activity in normoxic CSCs was enhanced, whereas hypoxic CSCs were rarely altered. At the molecular level, the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of lactate oxidation, was found to be elevated in normoxic CSCs. Furthermore, PGC-1α knockdown markedly reduced the metastatic potential of normoxic CSCs. Notably, both the PGC-1α-mediated OXPHOS activity and metastatic potential were impaired when hypoxia-inducible factor-1α (HIF-1α) was activated in normoxic CSCs. Together, these findings provide a therapeutic strategy against tumor metastasis through the targeting of PGC-1α and, thus, the suppression of lactate-feeding OXPHOS in normoxic CSCs may improve the therapeutic benefit of patients with cancer, particularly CRC.
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