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Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing [Systems Biology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-05-11 , DOI: 10.1073/pnas.2102050118
Abhijeet P. Deshmukh, Suhas V. Vasaikar, Katarzyna Tomczak, Shubham Tripathi, Petra den Hollander, Emre Arslan, Priyanka Chakraborty, Rama Soundararajan, Mohit Kumar Jolly, Kunal Rai, Herbert Levine, Sendurai A. Mani

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.



中文翻译:

通过单细胞RNA测序鉴定EMT信号转导和基因调控网络[系统生物学]

上皮-间质转化(EMT)在正常发育和癌症进展过程中起着至关重要的作用。EMT由多种信号传导途径诱导,包括TGF-β,BMP,Wnt-β-catenin,NOTCH,Shh和受体酪氨酸激酶。在这项研究中,我们通过TGF-β1刺激对经历EMT的MCF10A细胞进行了单细胞RNA测序。我们的综合分析表明,细胞通过EMT的进度不同。使用EMT期间基因表达谱的伪时间聚类重建,我们发现了EMT信号通路的顺序和并行激活。我们还观察到了EMT期间的各种过渡细胞状态。我们确定了重要的微RNA和转录因子的表达驱动EMT的监管信号节点。使用随机电路扰动方法,我们证明,NOTCH信号通路是TGF-β诱导的EMT的关键驱动器。此外,我们证明与中间混合EMT状态相对应的伪时间簇的基因特征与不良的患者预后相关。总的来说,这项研究提供了对特定背景的癌症进展驱动因素的见解,并强调了EMT过程的复杂性。

更新日期:2021-05-03
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