NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype

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dc.citation.firstpage251en_US
dc.citation.issueNumber6en_US
dc.citation.journalTitleIntegrative Biologyen_US
dc.citation.lastpage263en_US
dc.citation.volumeNumber11en_US
dc.contributor.authorBocci, Federicoen_US
dc.contributor.authorTripathi, Satyendra C.en_US
dc.contributor.authorVilchez Mercedes, Samuel A.en_US
dc.contributor.authorGeorge, Jason Thomasen_US
dc.contributor.authorCasabar, Julian P.en_US
dc.contributor.authorWong, Pak Kinen_US
dc.contributor.authorHanash, Samir M.en_US
dc.contributor.authorLevine, Herberten_US
dc.contributor.authorOnuchic, José Nelsonen_US
dc.contributor.authorJolly, Mohit Kumaren_US
dc.date.accessioned2019-11-14T17:52:29Zen_US
dc.date.available2019-11-14T17:52:29Zen_US
dc.date.issued2019en_US
dc.description.abstractThe epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype – a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) – the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.en_US
dc.identifier.citationBocci, Federico, Tripathi, Satyendra C., Vilchez Mercedes, Samuel A., et al.. "NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype." <i>Integrative Biology,</i> 11, no. 6 (2019) Oxford University Press: 251-263. https://doi.org/10.1093/intbio/zyz021.en_US
dc.identifier.digitalzyz021en_US
dc.identifier.doihttps://doi.org/10.1093/intbio/zyz021en_US
dc.identifier.urihttps://hdl.handle.net/1911/107692en_US
dc.language.isoengen_US
dc.publisherOxford University Pressen_US
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/),en_US
dc.titleNRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotypeen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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