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Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing

Deshmukh, AP and Vasaikar, SV and Tomczak, K and Tripathi, S and Den Hollander, P and Arslan, E and Chakraborty, P and Soundararajan, R and Jolly, MK and Rai, K and Levine, H and Mani, SA (2021) Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing. In: Proceedings of the National Academy of Sciences of the United States of America, 118 (19).

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Official URL: https://doi.org/10.73/pnas.2102050118


The epithelial-to-mesenchymal transition (EMT) plays a critical role during normal development and in cancer progression. EMT is induced by various signaling pathways, including TGF-β, BMP,Wnt-β-catenin, NOTCH, Shh, and receptor tyrosine kinases. In this study, we performed single-cell RNA sequencing on MCF10A cells undergoing EMT by TGF-β1 stimulation. Our comprehensive analysis revealed that cells progress through EMT at different paces. Using pseudotime clustering reconstruction of gene-expression profiles during EMT, we found sequential and parallel activation of EMT signaling pathways. We also observed various transitional cellular states during EMT. We identified regulatory signaling nodes that drive EMT with the expression of important microRNAs and transcription factors. Using a random circuit perturbation methodology, we demonstrate that the NOTCH signaling pathway acts as a key driver of TGF-β-induced EMT. Furthermore, we demonstrate that the gene signatures of pseudotime clusters corresponding to the intermediate hybrid EMT state are associated with poor patient outcome. Overall, this study provides insight into context-specific drivers of cancer progression and highlights the complexities of the EMT process. © 2021 National Academy of Sciences. All rights reserved.

Item Type: Journal Article
Publication: Proceedings of the National Academy of Sciences of the United States of America
Publisher: National Academy of Sciences
Additional Information: The copyright for this article belongs to National Academy of Sciences.
Keywords: beta1 integrin; beta5 integrin; epithelial cell adhesion molecule; microRNA; transcription factor; transforming growth factor beta1; uvomorulin; Notch receptor; Notch1 receptor; transcription factor Yap1; transcriptome; transforming growth factor beta; microRNA; transforming growth factor beta1, Article; breast epithelium cell; cancer growth; CDH1 gene; CDH2 gene; clinical article; cohort analysis; controlled study; EPCAM gene; epithelial mesenchymal transition; female; FN1 gene; gene; gene expression profiling; gene regulatory network; human; human cell; mathematical model; molecular interaction; Notch signaling; signal transduction; single cell RNA seq; survival analysis; VIM1 gene; bioinformatics; cell cycle progression; cluster analysis; cytoskeleton; genetic analysis; genetic heterogeneity; glucose transport; MAPK signaling; MCF-10A cell line; molecular dynamics; oxidative phosphorylation; phenotype; priority journal; process optimization; progression free survival; protein expression; transcription regulation; cell line; classification; drug effect; epithelial mesenchymal transition; epithelium cell; genetics; Kaplan Meier method; metabolism; neoplasm; procedures; prognosis; proportional hazards model; signal transduction; single cell analysis, Cell Line; Epithelial Cells; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Gene Regulatory Networks; Humans; Kaplan-Meier Estimate; MicroRNAs; Neoplasms; Prognosis; Proportional Hazards Models; RNA-Seq; Signal Transduction; Single-Cell Analysis; Transforming Growth Factor beta1
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 16 Feb 2023 10:05
Last Modified: 16 Feb 2023 10:05
URI: https://eprints.iisc.ac.in/id/eprint/80365

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