4.8 Article

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

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2102050118

关键词

EMT; scRNA-seq; signaling cascade; NOTCH; RACIPE

资金

  1. NIH/National Cancer Institute [R01CA200970, 2R01CA155243]
  2. Cancer Prevention and Research Institute of Texas Grant [RP170172]
  3. Bowes Foundation
  4. NSF [PHY-1935762, PHY-2019745]
  5. National Cancer Institute Grant [1R01CA226269]
  6. Ramanujan Fellowship - Science and Engineering Research Board, Government of India [SB/S2/RJN-049/2018]
  7. Infosys Foundation, Bangalore

向作者/读者索取更多资源

This study identified the complexity of the EMT process by analyzing gene expression profiles during EMT progression. It demonstrated that NOTCH signaling pathway drives TGF-beta-induced EMT, and gene signatures corresponding to intermediate hybrid EMT state are associated with poor patient outcome.
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-beta, BMP, Wnt-beta-catenin, NOTCH, Shh, and receptor tyrosine kinases. In this study, we performed single-cell RNA sequencing on MCF10A cells undergoing EMT by TGF-beta 1 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-beta-induced EMT. Furthermore, we demonstrate that the gene signatures of pseudotime clusters corresponding to the intermediate hybrid EMT state are associated with poor patient out-come. Overall, this study provides insight into context-specific drivers of cancer progression and highlights the complexities of the EMT process.

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