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dc.contributor.authorKreuzaler, Peteren
dc.contributor.authorClarke, Matthew Aen
dc.contributor.authorBrown, Elizabeth Jen
dc.contributor.authorWilson, Catherineen
dc.contributor.authorKortlever, Roderiken
dc.contributor.authorPiterman, Niren
dc.contributor.authorLittlewood, Trevoren
dc.contributor.authorEvan, Gerarden
dc.contributor.authorFisher, Jasminen
dc.date.accessioned2019-10-14T23:30:31Z
dc.date.available2019-10-14T23:30:31Z
dc.date.issued2019-10-14en
dc.identifier.issn0027-8424
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/297821
dc.description.abstractCells with higher levels of Myc proliferate more rapidly and super-competitively eliminate neighbouring cells. Nonetheless, tumour cells in aggressive breast cancers typically exhibit significant and stable heterogeneity in their Myc levels, which correlates with refractoriness to therapy and poor prognosis. This suggests that Myc heterogeneity confers some selective advantage on breast tumour growth and progression. To investigate this, we created a traceable MMTV-Wnt1-driven in vivo chimeric mammary tumour model comprising an admixture of low Myc and reversibly switchable high Myc-expressing clones. We show that such tumours exhibit interclonal mutualism wherein cells with high Myc-expression facilitate tumour growth by promoting pro-tumourigenic stroma yet concomitantly suppress Wnt expression, which renders them dependent for survival on paracrine Wnt provided by low Myc-expressing clones. To identify any therapeutic vulnerabilities arising from such interdependency, we modelled Myc/Ras/p53/Wnt signalling crosstalk as an executable network for low Myc for high Myc clones, and for the two together. This executable mechanistic model replicated the observed interdependence of high-Myc and low-Myc clones and predicted a novel pharmacological vulnerability to co-inhibition of COX2 and MEK. This was confirmed experimentally. Our study illustrates the power of executable models in elucidating mechanisms driving tumour heterogeneity and offers an innovative strategy for identifying novel combination therapies tailored to the oligoclonal landscape of heterogenous tumours.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherNational Academy of Sciences
dc.rightsAll rights reserved
dc.rights.uri
dc.subjectAnimalsen
dc.subjectMiceen
dc.subjectMammary Neoplasms, Experimentalen
dc.subjectras Proteinsen
dc.subjectProto-Oncogene Proteins c-mycen
dc.subjectDrug Resistance, Neoplasmen
dc.subjectGenetic Heterogeneityen
dc.subjectModels, Theoreticalen
dc.subjectFemaleen
dc.subjectTumor Suppressor Protein p53en
dc.subjectWnt Signaling Pathwayen
dc.titleHeterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling.en
dc.typeArticle
prism.endingPage22408
prism.issueIdentifier44en
prism.publicationDate2019en
prism.publicationNameProceedings of the National Academy of Sciences of the United States of Americaen
prism.startingPage22399
prism.volume116en
dc.identifier.doi10.17863/CAM.44875
dcterms.dateAccepted2019-09-22en
rioxxterms.versionofrecord10.1073/pnas.1903485116en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-10-14en
dc.contributor.orcidClarke, Matthew A [0000-0002-2582-9689]
dc.contributor.orcidBrown, Elizabeth J [0000-0002-1629-0044]
dc.contributor.orcidWilson, Catherine [0000-0002-5333-0295]
dc.contributor.orcidPiterman, Nir [0000-0002-8242-5357]
dc.contributor.orcidLittlewood, Trevor [0000-0003-3475-1462]
dc.contributor.orcidEvan, Gerard [0000-0003-0412-1216]
dc.contributor.orcidFisher, Yasmin [0000-0003-4477-9047]
dc.identifier.eissn1091-6490
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (19013)
pubs.funder-project-idCancer Research UK (12077)
cam.orpheus.successThu Jan 30 10:38:44 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2020-04-14


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