Vilchez Mercedes, SA and Bocci, F and Ahmed, M and Eder, I and Zhu, N and Levine, H and Onuchic, JN and Jolly, MK and Wong, PK (2022) Nrf2 Modulates the Hybrid Epithelial/Mesenchymal Phenotype and Notch Signaling During Collective Cancer Migration. In: Frontiers in Molecular Biosciences, 9 .
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Abstract
Hybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and resistance to therapy, appears to be central to this process. Here, using a combination of immunocytochemistry, single cell biosensors, and computational modeling, we show that Nrf2 functions as a phenotypic stability factor for hybrid E/M cells by inhibiting a complete epithelial-mesenchymal transition (EMT) during collective cancer migration. We also demonstrate that Nrf2 and EMT signaling are spatially coordinated near the leading edge. In particular, computational analysis of an Nrf2-EMT-Notch network and experimental modulation of Nrf2 by pharmacological treatment or CRISPR/Cas9 gene editing reveal that Nrf2 stabilizes a hybrid E/M phenotype which is maximally observed in the interior region immediately behind the leading edge. We further demonstrate that the Nrf2-EMT-Notch network enhances Dll4 and Jagged1 expression at the leading edge, which correlates with the formation of leader cells and protruding tips. Altogether, our results provide direct evidence that Nrf2 acts as a phenotypic stability factor in restricting complete EMT and plays an important role in coordinating collective cancer migration. Copyright © 2022 Vilchez Mercedes, Bocci, Ahmed, Eder, Zhu, Levine, Onuchic, Jolly and Wong.
| Item Type: | Journal Article |
|---|---|
| Publication: | Frontiers in Molecular Biosciences |
| Publisher: | Frontiers Media S.A. |
| Additional Information: | The copyright for this article belongs to Authors |
| Department/Centre: | Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering |
| Date Deposited: | 19 May 2022 07:19 |
| Last Modified: | 19 May 2022 07:19 |
| URI: | https://eprints.iisc.ac.in/id/eprint/72041 |
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