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.