Numb prevents a complete epithelial–mesenchymal transition by modulating Notch signalling

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dc.citation.issueNumber136en_US
dc.citation.journalTitleJournal of the Royal Society Interfaceen_US
dc.citation.volumeNumber14en_US
dc.contributor.authorBocci, Federicoen_US
dc.contributor.authorJolly, Mohit K.en_US
dc.contributor.authorTripathi, Satyendra C.en_US
dc.contributor.authorAguilar, Mitzien_US
dc.contributor.authorHanash, Samir M.en_US
dc.contributor.authorLevine, Herberten_US
dc.contributor.authorOnuchic, José Nelsonen_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2017-12-19T15:24:08Zen_US
dc.date.available2017-12-19T15:24:08Zen_US
dc.date.issued2017en_US
dc.description.abstractEpithelial–mesenchymal transition (EMT) plays key roles during embryonic development, wound healing and cancer metastasis. Cells in a partial EMT or hybrid epithelial/mesenchymal (E/M) phenotype exhibit collective cell migration, forming clusters of circulating tumour cells—the primary drivers of metastasis. Activation of cell–cell signalling pathways such as Notch fosters a partial or complete EMT, yet the mechanisms enabling cluster formation remain poorly understood. Using an integrated computational–experimental approach, we examine the role of Numb—an inhibitor of Notch intercellular signalling—in mediating EMT and clusters formation. We show via an mathematical model that Numb inhibits a full EMT by stabilizing a hybrid E/M phenotype. Consistent with this observation, knockdown of Numb in stable hybrid E/M cells H1975 results in a full EMT, thereby showing that Numb acts as a brake for a full EMT and thus behaves as a ‘phenotypic stability factor' by modulating Notch-driven EMT. By generalizing the mathematical model to a multi-cell level, Numb is predicted to alter the balance of hybrid E/M versus mesenchymal cells in clusters, potentially resulting in a higher tumour-initiation ability. Finally, Numb correlates with a worse survival in multiple independent lung and ovarian cancer datasets, hence confirming its relationship with increased cancer aggressiveness.en_US
dc.identifier.citationBocci, Federico, Jolly, Mohit K., Tripathi, Satyendra C., et al.. "Numb prevents a complete epithelial–mesenchymal transition by modulating Notch signalling." <i>Journal of the Royal Society Interface,</i> 14, no. 136 (2017) The Royal Society: https://doi.org/10.1098/rsif.2017.0512.en_US
dc.identifier.digital20170512-fullen_US
dc.identifier.doihttps://doi.org/10.1098/rsif.2017.0512en_US
dc.identifier.urihttps://hdl.handle.net/1911/98891en_US
dc.language.isoengen_US
dc.publisherThe Royal Societyen_US
dc.rightsPublished by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleNumb prevents a complete epithelial–mesenchymal transition by modulating Notch signallingen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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