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1. Inference of Intercellular Communications and Multilayer Gene-Regulations of Epithelial–Mesenchymal Transition From Single-Cell Transcriptomic Data

   https://doi.org/10.3389/fgene.2020.604585  

   Sha, Yutong; Wang, Shuxiong; Bocci, Federico; Zhou, Peijie; Nie, Qing (January 2021, Frontiers in Genetics)

   null (Ed.)

   Epithelial-to-mesenchymal transition (EMT) plays an important role in many biological processes during development and cancer. The advent of single-cell transcriptome sequencing techniques allows the dissection of dynamical details underlying EMT with unprecedented resolution. Despite several single-cell data analysis on EMT, how cell communicates and regulates dynamics along the EMT trajectory remains elusive. Using single-cell transcriptomic datasets, here we infer the cell–cell communications and the multilayer gene–gene regulation networks to analyze and visualize the complex cellular crosstalk and the underlying gene regulatory dynamics along EMT. Combining with trajectory analysis, our approach reveals the existence of multiple intermediate cell states (ICSs) with hybrid epithelial and mesenchymal features. Analyses on the time-series datasets from cancer cell lines with different inducing factors show that the induced EMTs are context-specific: the EMT induced by transforming growth factor B1 (TGFB1) is synchronous, whereas the EMTs induced by epidermal growth factor and tumor necrosis factor are asynchronous, and the responses of TGF-β pathway in terms of gene expression regulations are heterogeneous under different treatments or among various cell states. Meanwhile, network topology analysis suggests that the ICSs during EMT serve as the signaling in cellular communication under different conditions. Interestingly, our analysis of a mouse skin squamous cell carcinoma dataset also suggests regardless of the significant discrepancy in concrete genes between in vitro and in vivo EMT systems, the ICSs play dominant role in the TGF-β signaling crosstalk. Overall, our approach reveals the multiscale mechanisms coupling cell–cell communications and gene–gene regulations responsible for complex cell-state transitions. 

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

   https://doi.org/10.1073/pnas.2102050118  

   Deshmukh, Abhijeet P.; Vasaikar, Suhas V.; Tomczak, Katarzyna; Tripathi, Shubham; den Hollander, Petra; Arslan, Emre; Chakraborty, Priyanka; Soundararajan, Rama; Jolly, Mohit Kumar; Rai, Kunal; et al (May 2021, Proceedings of the National Academy of Sciences)

   null (Ed.)

   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. 

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3. Modeling the dynamics of EMT reveals genes associated with pan-cancer intermediate states and plasticity

   https://doi.org/10.1038/s41540-025-00512-2  

   McDermott, MeiLu; Mehta, Riddhee; Roussos_Torres, Evanthia; MacLean, Adam L (April 2025, npj Systems Biology and Applications)

   Epithelial–mesenchymal transition (EMT) is a cell state transition co-opted by cancer that drives metastasis via stable intermediate states. Here we study EMT dynamics to identify marker genes of highly metastatic intermediate cells via mathematical modeling with single-cell RNA sequencing (scRNA-seq) data. Across multiple tumor types and stimuli, we identified genes consistently upregulated in EMT intermediate states, many previously unrecognized as EMT markers. Bayesian parameter inference of a simple EMT mathematical model revealed tumor-specific transition rates, providing a framework to quantify EMT progression. Consensus analysis of differential expression, RNA velocity, and model-derived dynamics highlightedSFNandNRG1as key regulators of intermediate EMT. Independent validation confirmedSFNas an intermediate state marker. Our approach integrates modeling and inference to identify genes associated with EMT dynamics, offering biomarkers and therapeutic targets to modulate tumor-promoting cell state transitions driven by EMT. 

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4. Dual role of CASP8AP2/FLASH in regulating epithelial-to-mesenchymal transition plasticity (EMP)

   https://doi.org/10.1016/j.tranon.2023.101837  

   Catalanotto, Madison; Vaz, Joel Markus; Abshire, Camille; Youngblood, Reneau; Chu, Min; Levine, Herbert; Jolly, Mohit Kumar; Dragoi, Ana-Maria (January 2024, Translational Oncology)

   Epithelial-to-mesenchymal transition (EMT) is a developmental program that consists of the loss of epithelial features concomitant with the acquisition of mesenchymal features. Activation of EMT in cancer facilitates the acquisition of aggressive traits and cancer invasion. EMT plasticity (EMP), the dynamic transition between multiple hybrid states in which cancer cells display both epithelial and mesenchymal markers, confers survival advantages for cancer cells in constantly changing environments during metastasis. 

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5. Nrf2 Modulates the Hybrid Epithelial/Mesenchymal Phenotype and Notch Signaling During Collective Cancer Migration

   https://doi.org/10.3389/fmolb.2022.807324  

   Vilchez Mercedes, Samuel A.; Bocci, Federico; Ahmed, Mona; Eder, Ian; Zhu, Ninghao; Levine, Herbert; Onuchic, José N.; Jolly, Mohit Kumar; Wong, Pak Kin (April 2022, Frontiers in Molecular Biosciences)

   Hybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and resistance to therapy, appears to be central to this process. Here, using a combination of immunocytochemistry, single cell biosensors, and computational modeling, we show that Nrf2 functions as a phenotypic stability factor for hybrid E/M cells by inhibiting a complete epithelial-mesenchymal transition (EMT) during collective cancer migration. We also demonstrate that Nrf2 and EMT signaling are spatially coordinated near the leading edge. In particular, computational analysis of an Nrf2-EMT-Notch network and experimental modulation of Nrf2 by pharmacological treatment or CRISPR/Cas9 gene editing reveal that Nrf2 stabilizes a hybrid E/M phenotype which is maximally observed in the interior region immediately behind the leading edge. We further demonstrate that the Nrf2-EMT-Notch network enhances Dll4 and Jagged1 expression at the leading edge, which correlates with the formation of leader cells and protruding tips. Altogether, our results provide direct evidence that Nrf2 acts as a phenotypic stability factor in restricting complete EMT and plays an important role in coordinating collective cancer migration. 

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