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

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dc.citation.firstpage251
dc.citation.issueNumber6
dc.citation.journalTitleIntegrative Biology
dc.citation.lastpage263
dc.citation.volumeNumber11
dc.contributor.authorBocci, Federico
dc.contributor.authorTripathi, Satyendra C.
dc.contributor.authorVilchez Mercedes, Samuel A.
dc.contributor.authorGeorge, Jason Thomas
dc.contributor.authorCasabar, Julian P.
dc.contributor.authorWong, Pak Kin
dc.contributor.authorHanash, Samir M.
dc.contributor.authorLevine, Herbert
dc.contributor.authorOnuchic, José Nelson
dc.contributor.authorJolly, Mohit Kumar
dc.date.accessioned2019-11-14T17:52:29Z
dc.date.available2019-11-14T17:52:29Z
dc.date.issued2019
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’.
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.
dc.identifier.digitalzyz021
dc.identifier.doihttps://doi.org/10.1093/intbio/zyz021
dc.identifier.urihttps://hdl.handle.net/1911/107692
dc.language.isoeng
dc.publisherOxford University Press
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.
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/),
dc.titleNRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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