Measuring and Modelling the Epithelial Mesenchymal Hybrid State in Cancer: Clinical Implications

The epithelial-mesenchymal (E/M) hybrid state has emerged as an important mediator of the elements of cancer progression facilitated by epithelial mesenchymal plasticity (EMP). We review here the evidence for the presence and prognostic potential of E/M hybrid state in carcinoma, modelling predictions and validations studies to demonstrate stabilised E/M hybrid intermediates along the spectrum of EMP, and computational approaches for characterising and quantifying EMP phenotypes, with particular attention to the emerging realm of single-cell approaches through RNA sequencing and protein-based approaches.

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Measuring and Modelling the Epithelial- Mesenchymal Hybrid State in Cancer: Clinical Implications

Cells Tissues Organs ◽

10.1159/000515289 ◽

2021 ◽

pp. 1-24

Author(s):

Mohit Kumar Jolly ◽

Ryan J. Murphy ◽

Sugandha Bhatia ◽

Holly J. Whitfield ◽

Andrew Redfern ◽

...

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Cancer Progression ◽

Validation Studies ◽

Therapeutic Potential ◽

Prognostic Significance ◽

Clinical Implications ◽

Computational Approaches ◽

Hybrid State ◽

Important Mediator

The epithelial-mesenchymal (E/M) hybrid state has emerged as an important mediator of elements of cancer progression, facilitated by epithelial mesenchymal plasticity (EMP). We review here evidence for the presence, prognostic significance, and therapeutic potential of the E/M hybrid state in carcinoma. We further assess modelling predictions and validation studies to demonstrate stabilised E/M hybrid states along the spectrum of EMP, as well as computational approaches for characterising and quantifying EMP phenotypes, with particular attention to the emerging realm of single-cell approaches through RNA sequencing and protein-based techniques.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2102050118 ◽

2021 ◽

Vol 118 (19) ◽

pp. e2102050118

Author(s):

Abhijeet P. Deshmukh ◽

Suhas V. Vasaikar ◽

Katarzyna Tomczak ◽

Shubham Tripathi ◽

Petra den Hollander ◽

...

Keyword(s):

Single Cell ◽

Signaling Pathways ◽

Rna Sequencing ◽

Cancer Progression ◽

Tyrosine Kinases ◽

Regulatory Networks ◽

Expression Profiles ◽

Critical Role ◽

Mesenchymal Transition ◽

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 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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