NFATc Acts as a Non-Canonical Phenotypic Stability Factor for a Hybrid Epithelial/Mesenchymal Phenotype

Subbalakshmi, AR and Kundnani, D and Biswas, K and Ghosh, A and Hanash, SM and Tripathi, SC and Jolly, MK (2020) NFATc Acts as a Non-Canonical Phenotypic Stability Factor for a Hybrid Epithelial/Mesenchymal Phenotype. In: Frontiers in Oncology, 10 .

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Abstract

Metastasis remains the cause of over 90 of cancer-related deaths. Cells undergoing metastasis use phenotypic plasticity to adapt to their changing environmental conditions and avoid therapy and immune response. Reversible transitions between epithelial and mesenchymal phenotypes � epithelial�mesenchymal transition (EMT) and its reverse mesenchymal�epithelial transition (MET) � form a key axis of phenotypic plasticity during metastasis and therapy resistance. Recent studies have shown that the cells undergoing EMT/MET can attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes, the process of which is termed as partial EMT/MET. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either epithelial or mesenchymal state. Thus, it is crucial to identify the factors and regulatory networks enabling such hybrid E/M phenotypes. Here, employing an integrated computational-experimental approach, we show that the transcription factor nuclear factor of activated T-cell (NFATc) can inhibit the process of complete EMT, thus stabilizing the hybrid E/M phenotype. It increases the range of parameters enabling the existence of a hybrid E/M phenotype, thus behaving as a phenotypic stability factor (PSF). However, unlike previously identified PSFs, it does not increase the mean residence time of the cells in hybrid E/M phenotypes, as shown by stochastic simulations; rather it enables the co-existence of epithelial, mesenchymal and hybrid E/M phenotypes and transitions among them. Clinical data suggests the effect of NFATc on patient survival in a tissue-specific or context-dependent manner. Together, our results indicate that NFATc behaves as a non-canonical PSF for a hybrid E/M phenotype. © Copyright © 2020 Subbalakshmi, Kundnani, Biswas, Ghosh, Hanash, Tripathi and Jolly.

Item Type:	Journal Article
Publication:	Frontiers in Oncology
Publisher:	Frontiers Media S.A.
Additional Information:	Copyright © 2020 Subbalakshmi, Kundnani, Biswas, Ghosh, Hanash, Tripathi and Jolly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	14 Mar 2021 06:22
Last Modified:	14 Mar 2021 06:22
URI:	http://eprints.iisc.ac.in/id/eprint/66754

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