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. • Single-cell tracking of tumor organoids maps cell-type transitions and metabolism • Cancer stem and differentiated cells vary in glycolytic rates and exchange lactate • Lactate drives cancer stem cell identity by disrupting cell fate commitment • Lactate metabolism epigenetically activates the MYC oncogene Using fluorescent reporters and machine learning, Nguyen et al. traced cell types, metabolism, and lineages in tumor organoids, revealing that lactate regulates tumor development by inhibiting cancer cell differentiation and promoting dedifferentiation into a stem cell state. Mechanistically, lactate-induced metabolic reprogramming enhances histone acetylation, epigenetically activating MYC, shaping tumor dynamics.