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Metabolic memory underlying minimal residual disease in breast cancer.

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cam.issuedOnline2021-10-25
dc.contributor.authorRadic Shechter, Ksenija
dc.contributor.authorKafkia, Eleni
dc.contributor.authorZirngibl, Katharina
dc.contributor.authorGawrzak, Sylwia
dc.contributor.authorAlladin, Ashna
dc.contributor.authorMachado, Daniel
dc.contributor.authorLüchtenborg, Christian
dc.contributor.authorSévin, Daniel C
dc.contributor.authorBrügger, Britta
dc.contributor.authorPatil, Kiran R
dc.contributor.authorJechlinger, Martin
dc.contributor.orcidRadic Shechter, Ksenija [0000-0003-3139-9184]
dc.contributor.orcidZirngibl, Katharina [0000-0002-7518-0339]
dc.contributor.orcidGawrzak, Sylwia [0000-0002-7047-3319]
dc.contributor.orcidMachado, Daniel [0000-0002-2063-5383]
dc.contributor.orcidPatil, Kiran R [0000-0002-6166-8640]
dc.contributor.orcidJechlinger, Martin [0000-0002-3710-4466]
dc.date.accessioned2022-01-06T11:50:08Z
dc.date.available2022-01-06T11:50:08Z
dc.date.issued2021-10
dc.date.updated2022-01-06T11:50:07Z
dc.descriptionFunder: European Molecular Biology Laboratory
dc.descriptionFunder: European Molecular Biology Laboratory (EMBL)
dc.description.abstractTumor 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.
dc.identifier.doi10.17863/CAM.79595
dc.identifier.eissn1744-4292
dc.identifier.issn1744-4292
dc.identifier.otherPMC8543468
dc.identifier.other34694069
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332149
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.15252/msb.202010141
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1744-4292
dc.sourcenlmid: 101235389
dc.subjectglycolysis
dc.subjectmetabolic modeling
dc.subjectmulti-omics integration
dc.subjectoncogenic memory
dc.subjectorganoids
dc.subjectAnimals
dc.subjectBreast Neoplasms
dc.subjectFemale
dc.subjectHumans
dc.subjectMice
dc.subjectNeoplasm Recurrence, Local
dc.subjectNeoplasm, Residual
dc.titleMetabolic memory underlying minimal residual disease in breast cancer.
dc.typeArticle
dcterms.dateAccepted2021-09-29
prism.issueIdentifier10
prism.publicationNameMol Syst Biol
prism.volume17
pubs.funder-project-idEC | H2020 | H2020 Priority Excellent Science | H2020 Marie Skodowska-Curie Actions (MSCA) (664726)
pubs.funder-project-idMarie Curie (Marie Curie Cancer Care) (PCIG-GA--2011-294121)
pubs.funder-project-idDeutsche Forschungsgemeinschaft (DFG) (331351713 - SFB1324, 112927078 - TRR83)
pubs.funder-project-idMarie Curie (PCIG‐GA‐‐2011‐294121)
pubs.funder-project-idUKRI | Medical Research Council (MRC) (MC_UU_00025/11)
pubs.funder-project-idMedical Research Council (MC_UU_00025/11)
pubs.funder-project-idDeutsche Forschungsgemeinschaft (112927078 ‐ TRR83, 331351713 ‐ SFB1324)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.15252/msb.202010141

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