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- Title
NFATc Acts as a Non-Canonical Phenotypic Stability Factor for a Hybrid Epithelial/Mesenchymal Phenotype.
- Authors
Subbalakshmi, Ayalur Raghu; Kundnani, Deepali; Biswas, Kuheli; Ghosh, Anandamohan; Hanash, Samir M.; Tripathi, Satyendra C.; Jolly, Mohit Kumar
- 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.
- Subjects
EPITHELIAL-mesenchymal transition; PHENOTYPES; PHENOTYPIC plasticity; REVERSIBLE phase transitions; TRANSCRIPTION factors
- Publication
Frontiers in Oncology, 2020, Vol 10, pN.PAG
- ISSN
2234-943X
- Publication type
Article
- DOI
10.3389/fonc.2020.553342