Lactate controls cancer stemness and plasticity through epigenetic regulation.

Tumours arise from uncontrolled cell proliferation driven by mutations in genes that regulate stem cell renewal and differentiation. Intestinal tumours, 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 fluorescent metabolic and signalling reporters in human tumour organoids, combined with our machine learning-based cell tracker, CellPhenTracker, we simultaneously traced cell type specification, metabolic changes, and reconstructed cell lineage trajectories during tumour organoid development. Our findings reveal distinctive metabolic phenotypes in CSCs and CDCs. We find that lactate regulates tumour 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 BRD4, targeting cancer metabolism combined with BET inhibitors emerges as a promising strategy to prevent tumour relapse.