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dc.contributor.authorBuczacki, Simonen
dc.contributor.authorPopova, Semiramisen
dc.contributor.authorBiggs, Emmaen
dc.contributor.authorKoukorava, Chrysaen
dc.contributor.authorBuzzelli, Jonen
dc.contributor.authorVermeulen, Louisen
dc.contributor.authorHazelwood, Leeen
dc.contributor.authorFrancies, Hayleyen
dc.contributor.authorGarnett, Mathew Jen
dc.contributor.authorWinton, Douglasen
dc.date.accessioned2018-09-05T12:43:41Z
dc.date.available2018-09-05T12:43:41Z
dc.date.issued2018-07en
dc.identifier.issn0022-1007
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/279436
dc.description.abstractCellular dormancy and heterogeneity in cell cycle length provide important explanations for treatment failure following adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC) yet the molecular control of the dormant versus cycling state remains unknown. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumour cells. Unexpectedly, we demonstrate, that dormant CRC cells are differentiated yet retain clonogenic capacity. Murine organoid drug screening identifies itraconazole generates spheroid collapse and loss of dormancy. Human CRC cell dormancy and tumour growth can also be perturbed by itraconazole, which is found to inhibit Wnt signalling through non-canonical hedgehog signalling. Pre-clinical validation shows itraconazole to be effective in multiple assays through Wnt inhibition, causing both cycling and dormant cells to switch to global senescence. These data provide pre-clinical evidence to support an early-phase trial of itraconazole in CRC
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherRockefeller University Press
dc.rightsAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectOrganoidsen
dc.subjectCell Line, Tumoren
dc.subjectSpheroids, Cellularen
dc.subjectAnimalsen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectColorectal Neoplasmsen
dc.subjectItraconazoleen
dc.subjectReceptors, G-Protein-Coupleden
dc.subjectCell Separationen
dc.subjectStaining and Labelingen
dc.subjectCell Cycleen
dc.subjectCell Differentiationen
dc.subjectCell Proliferationen
dc.subjectPhenotypeen
dc.subjectNeoplastic Stem Cellsen
dc.subjectWnt Signaling Pathwayen
dc.subjectCell Cycle Checkpointsen
dc.subjectCellular Senescenceen
dc.titleItraconazole targets cell cycle heterogeneity in colorectal cancer.en
dc.typeArticle
prism.endingPage1912
prism.issueIdentifier7en
prism.publicationDate2018en
prism.publicationNameThe Journal of experimental medicineen
prism.startingPage1891
prism.volume215en
dc.identifier.doi10.17863/CAM.26810
dcterms.dateAccepted2018-05-10en
rioxxterms.versionofrecord10.1084/jem.20171385en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-07en
dc.contributor.orcidBuczacki, Simon [0000-0002-2975-416X]
dc.contributor.orcidPopova, Semiramis [0000-0002-3200-4247]
dc.contributor.orcidWinton, Douglas [0000-0001-6067-7927]
dc.identifier.eissn1540-9538
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (16485)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)