2. Academic Validation
  3. Lactate controls cancer stemness and plasticity through epigenetic regulation

Lactate controls cancer stemness and plasticity through epigenetic regulation

  • Cell Metab. 2025 Apr 1;37(4):903-919.e10. doi: 10.1016/j.cmet.2025.01.002.
Nguyen T B Nguyen 1,  Sira Gevers 1,  Rutger N U Kok 1,  Lotte M Burgering 1,  Hannah Neikes 2,  Ninouk Akkerman 3,  Max A Betjes 4,  Marlies C Ludikhuize 5,  Can Gulersonmez 5,  Edwin C A Stigter 5,  Yvonne Vercoulen 5,  Jarno Drost 6,  Hans Clevers 7,  Michiel Vermeulen 2,  Jeroen S van Zon 4,  Sander J Tans 8,  Boudewijn M T Burgering 1,  Maria J Rodríguez Colman 9
Affiliations

Affiliations

  • 1 Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
  • 2 Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen 6525 GA, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
  • 3 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 4 AMOLF, Amsterdam, the Netherlands.
  • 5 Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands.
  • 6 Oncode Institute, Utrecht, the Netherlands; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands.
  • 7 Oncode Institute, Utrecht, the Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 8 AMOLF, Amsterdam, the Netherlands; Bionanoscience Department, Kavli Institute of Nanoscience Delft, Delft University of Technology, Delft, the Netherlands.
  • 9 Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. Electronic address: m.j.rodriguezcolman@umcutrecht.nl.
PMID: 39933514 DOI: 10.1016/j.cmet.2025.01.002
Abstract

Tumors arise from uncontrolled cell proliferation driven by mutations in genes that regulate stem cell renewal and differentiation. Intestinal tumors, however, retain some hierarchical organization, maintaining both Cancer Stem Cells (CSCs) and Cancer differentiated cells (CDCs). This heterogeneity, coupled with cellular plasticity enabling CDCs to revert to CSCs, contributes to therapy resistance and relapse. Using genetically encoded fluorescent reporters in human tumor organoids, combined with our machine-learning-based cell tracker, CellPhenTracker, we simultaneously traced cell-type specification, metabolic changes, and reconstructed cell lineage trajectories during tumor Organoid development. Our findings reveal distinctive metabolic phenotypes in CSCs and CDCs. We find that lactate regulates tumor dynamics, suppressing CSC differentiation and inducing dedifferentiation into a proliferative CSC state. Mechanistically, lactate increases histone acetylation, epigenetically activating MYC. Given that lactate's regulation of MYC depends on the bromodomain-containing protein 4 (BRD4), targeting Cancer metabolism and BRD4 inhibitors emerge as a promising strategy to prevent tumor relapse.

Keywords

cancer metabolism; cell plasticity; cell types; cell-cell interactions; differentiation; heterogeneity; live imaging; organoids; single-cell tracking; stem cells.

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