Metabolic memory underlying minimal residual disease in breast cancer.

Tumor relapse from treatment‐resistant cells (minimal residual disease, MRD) underlies most breast cancer‐related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi‐omics data from a tractable organoid system with a metabolic modeling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non‐proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzyme reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo‐adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment‐resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small‐molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post‐treatment care to prevent breast tumor recurrence. SYNOPSIS: Despite their normal morphology and non‐proliferative phenotype, treatment‐resistant breast cancer cells retain epigenetic imprinting and metabolic characteristics of their prior tumour state. Multi‐omics analysis and flux modelling reveals elevated glycolysis and abnormal urea cycle pathway activity in residual cells (Minimal Residual Disease, MRD).Transcriptome data from human samples also indicate elevated glycolysis of MRD.In contrast to normal epithelial cells and cancer, MRD is dependent on glycolysis for survival and can be selectively targeted using a small‐molecule inhibitor.Epigenetic similarity between MRD‐ and tumour‐cells suggests a mechanistic basis for metabolic memory. [ABSTRACT FROM AUTHOR]