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...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
29 September 2021
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| In: |
Molecular systems biology
Year: 2021, Volume: 17, Issue: 10, Pages: 1-21 |
| ISSN: | 1744-4292 |
| DOI: | 10.15252/msb.202010141 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.15252/msb.202010141 Verlag, lizenzpflichtig, Volltext: https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=DOISource&SrcApp=WOS&KeyAID=10.15252%2Fmsb.202010141&DestApp=DOI&SrcAppSID=C3vor5GMCJilxsEqfPX&SrcJTitle=MOLECULAR+SYSTEMS+BIOLOGY&DestDOIRegistrantName=EMBO 
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| Author Notes: | Ksenija Radic Shechter, Eleni Kafkia, Katharina Zirngibl, Sylwia Gawrzak, Ashna Alladin, Daniel Machado, Christian Luechtenborg, Daniel C. Sevin, Britta Bruegger, Kiran R. Patil and Martin Jechlinger |
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| 520 | |a 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. | ||
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