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

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dc.citation.issueNumber136
dc.citation.journalTitleJournal of the Royal Society Interface
dc.citation.volumeNumber14
dc.contributor.authorBocci, Federico
dc.contributor.authorJolly, Mohit K.
dc.contributor.authorTripathi, Satyendra C.
dc.contributor.authorAguilar, Mitzi
dc.contributor.authorHanash, Samir M.
dc.contributor.authorLevine, Herbert
dc.contributor.authorOnuchic, José Nelson
dc.contributor.orgCenter for Theoretical Biological Physics
dc.date.accessioned2017-12-19T15:24:08Z
dc.date.available2017-12-19T15:24:08Z
dc.date.issued2017
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.
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.
dc.identifier.digital20170512-full
dc.identifier.doihttps://doi.org/10.1098/rsif.2017.0512
dc.identifier.urihttps://hdl.handle.net/1911/98891
dc.language.isoeng
dc.publisherThe Royal Society
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.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleNumb prevents a complete epithelial–mesenchymal transition by modulating Notch signalling
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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