Metabolic memory underlying minimal residual disease in breast cancer.
glycolysis
metabolic modeling
multi-omics integration
oncogenic memory
organoids
Journal
Molecular systems biology
ISSN: 1744-4292
Titre abrégé: Mol Syst Biol
Pays: England
ID NLM: 101235389
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
23
09
2021
received:
24
11
2020
accepted:
29
09
2021
entrez:
25
10
2021
pubmed:
26
10
2021
medline:
27
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34694069
doi: 10.15252/msb.202010141
pmc: PMC8543468
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e10141Subventions
Organisme : Medical Research Council
ID : MC_UU_00025/11
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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