Lactate controls cancer stemness and plasticity through epigenetic regulation
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.
Authors
- Max A. Betjes (ORCID: https://orcid.org/0000-0001-6992-9975)
- Nguyen T.B. Nguyen
- Maria J. Rodríguez Colman (ORCID: https://orcid.org/0000-0001-8382-5128)
- Edwin C.A. Stigter (ORCID: https://orcid.org/0000-0001-5970-4668)
- Lotte M Burgering
- Boudewijn Burgering (ORCID: https://orcid.org/0000-0002-4044-9596)
- Jeroen S. van Zon (ORCID: https://orcid.org/0000-0002-6021-2924)
- Marlies C. Ludikhuize
- Sira Gevers
- Jarno Drost (ORCID: https://orcid.org/0000-0002-2941-6179)
- Sander J. Tans (ORCID: https://orcid.org/0000-0002-7131-2568)
- Can Gulersonmez
- Hans Clevers (ORCID: https://orcid.org/0000-0002-3077-5582)
- Rutger N.U. Kok (ORCID: https://orcid.org/0000-0002-6214-681X)
- Hannah K. Neikes
- Michiel Vermeulen (ORCID: https://orcid.org/0000-0003-0836-6894)
- Ninouk Akkerman (ORCID: https://orcid.org/0000-0003-0547-3993)
- Yvonne Vercoulen (ORCID: https://orcid.org/0000-0002-5060-2603)
Institutions
- Royal Netherlands Academy of Arts and Sciences (NL)
- Radboud University Nijmegen (NL)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Radboud University Medical Center (NL)
- Institute for Atomic and Molecular Physics (NL)
- University Medical Center Utrecht (NL)
- Radboud Institute for Molecular Life Sciences (NL)
- Oncode Institute (NL)
- Princess Máxima Center (NL)
- Delft University of Technology (NL)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2025-02-10
- DOI
- https://doi.org/10.1016/j.cmet.2025.01.002
- Citations
- 52
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 41.91
Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Universitair Medisch Centrum Utrecht
- KWF Kankerbestrijding
- Oncode Institute