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dc.contributor.authorBocci, Federico
Tripathi, Satyendra C.
Vilchez Mercedes, Samuel A.
George, Jason T.
Casabar, Julian P.
Wong, Pak Kin
Hanash, Samir M.
Levine, Herbert
Onuchic, José N.
Jolly, Mohit Kumar
dc.date.accessioned 2019-11-14T17:52:29Z
dc.date.available 2019-11-14T17:52:29Z
dc.date.issued 2019
dc.identifier.citation Bocci, 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." Integrative Biology, 11, no. 6 (2019) Oxford University Press: 251-263. https://doi.org/10.1093/intbio/zyz021.
dc.identifier.urihttps://hdl.handle.net/1911/107692
dc.description.abstract The 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.language.iso eng
dc.publisher Oxford 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.title NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype
dc.type Journal article
dc.citation.journalTitle Integrative Biology
dc.citation.volumeNumber 11
dc.citation.issueNumber 6
dc.identifier.digital zyz021
dc.type.dcmi Text
dc.identifier.doihttps://doi.org/10.1093/intbio/zyz021
dc.type.publication publisher version
dc.citation.firstpage 251
dc.citation.lastpage 263


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