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

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 sequenci...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS Jg. 118; H. 19
Hauptverfasser: Deshmukh, Abhijeet P, Vasaikar, Suhas V, Tomczak, Katarzyna, Tripathi, Shubham, den Hollander, Petra, Arslan, Emre, Chakraborty, Priyanka, Soundararajan, Rama, Jolly, Mohit Kumar, Rai, Kunal, Levine, Herbert, Mani, Sendurai A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 11.05.2021
Schlagworte:
Cell Line
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Epithelial-Mesenchymal Transition - drug effects
Epithelial-Mesenchymal Transition - genetics
Gene Expression Profiling - methods
Gene Expression Profiling - statistics & numerical data
Gene Regulatory Networks
Humans
Kaplan-Meier Estimate
MicroRNAs - genetics
Neoplasms - classification
Neoplasms - genetics
Prognosis
Proportional Hazards Models
RNA-Seq - methods
Signal Transduction - drug effects
Signal Transduction - genetics
Single-Cell Analysis - methods
Transforming Growth Factor beta1 - metabolism
Transforming Growth Factor beta1 - pharmacology
NOTCH
scRNA-seq
RACIPE
signaling cascade
EMT
ISSN:1091-6490, 1091-6490
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2102050118