@article {Bocci390237, author = {Federico Bocci and Satyendra C Tripathi and Samuel A Vilchez Mercedes and Jason T George and Julian P Casabar and Pak Kin Wong and Samir M Hanash and Herbert Levine and Jos{\'e} N Onuchic and Mohit Kumar Jolly}, title = {NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype}, elocation-id = {390237}, year = {2019}, doi = {10.1101/390237}, publisher = {Cold Spring Harbor Laboratory}, 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. Here, 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 destabilised 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 {\textquoteleft}metastatic sweet spot{\textquoteright}.}, URL = {https://www.biorxiv.org/content/early/2019/05/10/390237}, eprint = {https://www.biorxiv.org/content/early/2019/05/10/390237.full.pdf}, journal = {bioRxiv} }