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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
dc.contributor.authorJechlinger, Martin
dc.date.accessioned2021-10-25T11:11:05Z
dc.date.available2021-10-25T11:11:05Z
dc.date.issued2021-10
dc.date.submitted2020-11-24
dc.identifier.issn1744-4292
dc.identifier.othermsb202010141
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/329846
dc.descriptionFunder: European Molecular Biology Laboratory (EMBL); Id: http://dx.doi.org/10.13039/100013060
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.languageen
dc.publisherEMBO
dc.subjectEMBO03
dc.subjectEMBO21
dc.subjectArticle
dc.subjectArticles
dc.subjectglycolysis
dc.subjectmetabolic modeling
dc.subjectmulti‐omics integration
dc.subjectoncogenic memory
dc.subjectorganoids
dc.titleMetabolic memory underlying minimal residual disease in breast cancer.
dc.typeArticle
dc.date.updated2021-10-25T11:11:05Z
prism.issueIdentifier10
prism.publicationNameMol Syst Biol
prism.volume17
dc.identifier.doi10.17863/CAM.77291
dcterms.dateAccepted2021-09-29
rioxxterms.versionofrecord10.15252/msb.202010141
rioxxterms.versionAO
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
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 [0000-0002-6166-8640]
dc.contributor.orcidJechlinger, Martin [0000-0002-3710-4466]
dc.identifier.eissn1744-4292
pubs.funder-project-idUKRI | Medical Research Council (MRC) (MC_UU_00025/11)
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) (112927078 ‐ TRR83, 331351713 ‐ SFB1324)
cam.issuedOnline2021-10-25


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