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Metabolic memory underlying minimal residual disease in breast cancer.

Published version
Peer-reviewed

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Authors

Radic Shechter, Ksenija  ORCID logo  https://orcid.org/0000-0003-3139-9184
Kafkia, Eleni 
Zirngibl, Katharina  ORCID logo  https://orcid.org/0000-0002-7518-0339
Alladin, Ashna 

Abstract

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.

Description

Funder: European Molecular Biology Laboratory (EMBL); Id: http://dx.doi.org/10.13039/100013060

Keywords

EMBO03, EMBO21, Article, Articles, glycolysis, metabolic modeling, multi‐omics integration, oncogenic memory, organoids

Journal Title

Mol Syst Biol

Conference Name

Journal ISSN

1744-4292
1744-4292

Volume Title

17

Publisher

EMBO
Sponsorship
UKRI | Medical Research Council (MRC) (MC_UU_00025/11)
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) (112927078 ‐ TRR83, 331351713 ‐ SFB1324)