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

Bocci, Federico and Tripathi, Satyendra C and Mercedes, Samuel A Vilchez and George, Jason T and Casabar, Julian P and Wong, Pak Kin and Hanash, Samir M and Levine, Herbert and Onuchic, Jose N and Jolly, Mohit Kumar (2019) NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype. In: INTEGRATIVE BIOLOGY, 11 (6). pp. 251-263.

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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'.

Item Type:	Journal Article
Publication:	INTEGRATIVE BIOLOGY
Publisher:	OXFORD UNIV PRESS
Additional Information:	Copyright of this article belongs to OXFORD UNIV PRESS
Keywords:	E-CADHERIN; CANCER-CELLS; EMT; SULFORAPHANE; DEGRADATION; PLASTICITY; MIGRATION; INVASION; REDOX; ZEB1
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	10 Dec 2019 06:03
Last Modified:	10 Dec 2019 06:03
URI:	http://eprints.iisc.ac.in/id/eprint/63875

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