Wnt signalling is a bi-directional vulnerability of cancer cells

DC FieldValueLanguage
dc.contributor.authorDuffy, David J.-
dc.contributor.authorKrstic, Aleksandar-
dc.contributor.authorSchwarzl, Thomas-
dc.contributor.authorHalasz, Melinda-
dc.contributor.authorFey, Dirk-
dc.contributor.authorHaley, Bridget-
dc.contributor.authorWhilde, Jenny-
dc.contributor.authorHiggins, Desmond G-
dc.contributor.authorKolch, Walter-
dc.date.accessioned2019-04-02T11:44:55Z-
dc.date.available2019-04-02T11:44:55Z-
dc.date.copyright2016 the Authorsen_US
dc.date.issued2016-08-11-
dc.identifier.citationOncotargeten_US
dc.identifier.urihttp://hdl.handle.net/10197/9772-
dc.description.abstractWnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/β-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type. Hyper-activation directs cancer cells to undergo apoptosis, even in cells oncogenically driven by β-catenin. Wnt inhibition blocks proliferation of cancer cells and promotes neuroblastoma differentiation. Wnt and retinoic acid co-treatments synergise, representing a promising combination treatment for MYCN-amplified neuroblastoma. Additionally, we report novel cross-talks between MYCN and β-catenin signalling, which repress normal β-catenin mediated transcriptional regulation. A β-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This β-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/β-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.en_US
dc.description.sponsorshipEuropean Commission - Seventh Framework Programme (FP7)en_US
dc.description.sponsorshipScience Foundation Irelanden_US
dc.language.isoenen_US
dc.publisherImpact Journalsen_US
dc.rightsLicensed under a Creative Commons Attribution 3.0 License.en_US
dc.subjectMYC (c-MYC)en_US
dc.subjectColorectal canceren_US
dc.subjectmRNA sequencing (mRNA-seq)en_US
dc.subjectMelanomaen_US
dc.subjectNeuroblastomaen_US
dc.titleWnt signalling is a bi-directional vulnerability of cancer cellsen_US
dc.typeJournal Articleen_US
dc.statusPeer revieweden_US
dc.identifier.volume7en_US
dc.identifier.issue37en_US
dc.identifier.startpage60310en_US
dc.identifier.endpage60331en_US
dc.identifier.doi10.18632/oncotarget.11203-
dc.neeo.contributorDuffy|David J.|aut|-
dc.neeo.contributorKrstic|Aleksandar|aut|-
dc.neeo.contributorSchwarzl|Thomas|aut|-
dc.neeo.contributorHalasz|Melinda|aut|-
dc.neeo.contributorFey|Dirk|aut|-
dc.neeo.contributorHaley|Bridget|aut|-
dc.neeo.contributorWhilde|Jenny|aut|-
dc.neeo.contributorHiggins|Desmond G|aut|-
dc.neeo.contributorKolch|Walter|aut|-
dc.date.updated2017-12-06-
dc.identifier.grantid06/CE/B1129-
dc.identifier.grantid259348-2-
item.fulltextWith Fulltext-
item.grantfulltextopen-
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