Metabolic memory underlying minimal residual disease in breast cancer.

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Radic Shechter, Ksenija  ORCID logo
Kafkia, Eleni 
Zirngibl, Katharina  ORCID logo
Alladin, Ashna 

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.


Funder: European Molecular Biology Laboratory

Funder: European Molecular Biology Laboratory (EMBL)

glycolysis, metabolic modeling, multi-omics integration, oncogenic memory, organoids, Animals, Breast Neoplasms, Female, Humans, Mice, Neoplasm Recurrence, Local, Neoplasm, Residual
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Mol Syst Biol
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EC | H2020 | H2020 Priority Excellent Science | H2020 Marie Skodowska-Curie Actions (MSCA) (664726)
Marie Curie (Marie Curie Cancer Care) (PCIG-GA--2011-294121)
Deutsche Forschungsgemeinschaft (DFG) (331351713 - SFB1324, 112927078 - TRR83)
Marie Curie (PCIG‐GA‐‐2011‐294121)
UKRI | Medical Research Council (MRC) (MC_UU_00025/11)
Medical Research Council (MC_UU_00025/11)
Deutsche Forschungsgemeinschaft (112927078 ‐ TRR83, 331351713 ‐ SFB1324)