Dynamics of Phenotypic Heterogeneity Associated with EMT and Stemness during Cancer Progression

Jolly, Mohit Kumar; Celià-Terrassa, Toni

doi:10.3390/jcm8101542

Cited by 117 publications

(125 citation statements)

References 183 publications

(263 reference statements)

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“…Various attempts to characterize the spectrum of EMT at molecular and/or morphological levels have been made recently, enabled by latest developments in multiplex imaging, single-cell RNA-seq and inducible systems (Mandal et al, 2016;Pastushenko et al, 2018;Stylianou et al, 2018;Cook and Vanderhyden, 2019;Devaraj and Bose, 2019;Karacosta et al, 2019;Wang et al, 2019b;Watanabe et al, 2019). These approaches have highlighted the dynamical nature of EMT in driving cancer progression in patients (Jolly and Celia-Terrassa, 2019). Further, various approaches to quantify the EMT spectrum of samples based on different signatures of tumor types have been made (Foroutan et al, 2017;Puram et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Cells may take different routes in this multidimensional landscape as effectively captured by recent high-throughput dynamic approaches (Karacosta et al, 2019;Watanabe et al, 2019). Initially thought of as binary, EMT is now considered as a complex process involving one or more hybrid epithelial/mesenchymal (E/M) states (Jolly and Celia-Terrassa, 2019). These hybrid E/M states can be more plastic and tumorigenic than 'purely epithelial' or 'purely mesenchymal' ones, thus constituting the 'fittest' phenotype for metastasis (Grosse-Wilde et al, 2015;Bierie et al, 2017;Pastushenko et al, 2018;Kröger et al, 2019;Tripathi et al, 2019b).…”

Section: Introductionmentioning

confidence: 99%

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Comparative study of transcriptomics-based scoring metrics for the epithelial-hybrid-mesenchymal spectrum

Chakraborty

George

Tripathi

et al. 2020

Preprint

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The Epithelial-mesenchymal transition (EMT) is a cellular process implicated in embryonic development, wound healing, and pathological conditions such as cancer metastasis and fibrosis. Cancer cells undergoing EMT exhibit enhanced aggressive behavior characterized by drug resistance, tumor-initiation potential, and the ability to evade immune system. Recent in silico, in vitro, and in vivo evidence indicates that EMT is not an all-or-none process; instead, cells stably acquire one or more hybrid epithelial/ mesenchymal (E/M) phenotypes which often can be more aggressive than purely epithelial or mesenchymal cell populations. Thus, the EMT status of cancer cells can prove to be a critical estimate of patient prognosis. Recent attempts have employed different transcriptomics signatures to quantify EMT status in cell lines and patient tumors. However, a comprehensive comparison of these methods, including their accuracy in identifying cells in the hybrid E/M phenotype(s), is lacking. Here, we compare three distinct metrics that score EMT on a continuum, based on the transcriptomics signature of individual samples. Our results demonstrate that these methods exhibit good concordance among themselves in quantifying the extent of EMT in a given sample. Moreover, scoring EMT using any of the three methods discerned that cells undergo varying extents of EMT across tumor types. Separately, our analysis also identified tumor types with maximum variability in terms of EMT and associated an enrichment of hybrid E/M signatures in these samples. Moreover, we also found that the multinomial logistic regression (MLR) based metric was capable of distinguishing between 'pure' individual hybrid E/M vs. mixtures of epithelial (E) and mesenchymal (M) cells. Our results, thus, suggest that while any of the three methods can indicate a generic trend in the EMT status of a given cell, the MLR method has two additional advantages: a) it uses a small number of predictors to calculate the EMT score, and b) it can predict from the transcriptomic signature of a population whether it is comprised of 'pure' hybrid E/M cells at the single-cell level or is instead an ensemble of E and M cell subpopulations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative study of transcriptomics-based scoring metrics for the epithelial-hybrid-mesenchymal spectrum

Chakraborty

George

Tripathi

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Initially thought of as binary, EMT is now considered as a complex process involving one or more hybrid epithelial/mesenchymal (E/M) states (Jolly and Celia-Terrassa, 2019). These hybrid E/M states can be more plastic and tumorigenic than "purely E" or "purely M" ones, thus constituting the "fittest" phenotype for metastasis (Grosse-Wilde et al, 2015;Bierie et al, 2017;Pastushenko et al, 2018;Kröger et al, 2019;Tripathi et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Comparative Study of Transcriptomics-Based Scoring Metrics for the Epithelial-Hybrid-Mesenchymal Spectrum

Chakraborty

George

Tripathi

et al. 2020

Front. Bioeng. Biotechnol.

Self Cite

105

106

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The Epithelial-mesenchymal transition (EMT) is a cellular process implicated in embryonic development, wound healing, and pathological conditions such as cancer metastasis and fibrosis. Cancer cells undergoing EMT exhibit enhanced aggressive behavior characterized by drug resistance, tumor-initiation potential, and the ability to evade the immune system. Recent in silico, in vitro, and in vivo evidence indicates that EMT is not an all-or-none process; instead, cells can stably acquire one or more hybrid epithelial/mesenchymal (E/M) phenotypes which often can be more aggressive than purely E or M cell populations. Thus, the EMT status of cancer cells can prove to be a critical estimate of patient prognosis. Recent attempts have employed different transcriptomics signatures to quantify EMT status in cell lines and patient tumors. However, a comprehensive comparison of these methods, including their accuracy in identifying cells in the hybrid E/M phenotype(s), is lacking. Here, we compare three distinct metrics that score EMT on a continuum, based on the transcriptomics signature of individual samples. Our results demonstrate that these methods exhibit good concordance among themselves in quantifying the extent of EMT in a given sample. Moreover, scoring EMT using any of the three methods discerned that cells can undergo varying extents of EMT across tumor types. Separately, our analysis also identified tumor types with maximum variability in terms of EMT and associated an enrichment of hybrid E/M signatures in these samples. Moreover, we also found that the multinomial logistic regression (MLR)-based metric was capable of distinguishing between "pure" individual hybrid E/M vs. mixtures of E and M cells. Our results, thus, suggest that while any of the three methods can indicate a generic trend in the EMT status of a given cell, the MLR method has two additional advantages: (a) it uses a small number of predictors to calculate the EMT score and (b) it can predict from the transcriptomic signature of a population whether it is comprised of "pure" hybrid E/M cells at the single-cell level or is instead an ensemble of E and M cell subpopulations.

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“…Recent in vitro, in vivo and in silico investigations have emphasized the existence and significance of hybrid E/M phenotype(s) in various cancer types (36). These hybrid E/M phenotypes can exhibit maximum plasticity (37), possess traits of cancer stem cell-like traits, evade drug resistance, and thus be the 'fittest' for metastasis (7).…”

Section: Discussionmentioning

confidence: 99%

NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype

Subbalakshmi

Kundnani²,

Biswas

et al. 2020

Preprint

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Metastasis remains the cause of over 90% of cancer-related deaths. Cells undergoing metastasis use phenotypic plasticity to adapt to their changing environmental conditions and avoid therapy and immune response. Reversible transitions between epithelial and mesenchymal phenotypes -Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) -form a key axis of phenotypic plasticity during metastasis and therapy resistance. Recent studies have shown that the cells undergoing EMT/MET can attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes, the process of which is termed as partial EMT/MET. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either epithelial or mesenchymal state. Thus, it is crucial to identify the factors and regulatory networks enabling such hybrid E/M phenotypes. Here, employing an integrated computational-experimental approach, we show that the transcription factor NFATc can inhibit the process of complete EMT, thus stabilizing the hybrid E/M phenotype. It increases the range of parameters enabling the existence of a hybrid E/M phenotype, thus behaving as a phenotypic stability factor (PSF). However, unlike previously identified PSFs, it does not increase the mean residence time of the cells in hybrid E/M phenotypes, as shown by stochastic simulations; rather it enables the coexistence of epithelial, mesenchymal and hybrid E/M phenotypes and transitions among them. Clinical data suggests the effect of NFATc on patient survival in a tissue-specific or contextdependent manner. Together, our results indicate that NFATc behaves as a non-canonical phenotypic stability factor for a hybrid E/M phenotype.

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Dynamics of Phenotypic Heterogeneity Associated with EMT and Stemness during Cancer Progression

Cited by 117 publications

References 183 publications

Comparative study of transcriptomics-based scoring metrics for the epithelial-hybrid-mesenchymal spectrum

Comparative study of transcriptomics-based scoring metrics for the epithelial-hybrid-mesenchymal spectrum

Comparative Study of Transcriptomics-Based Scoring Metrics for the Epithelial-Hybrid-Mesenchymal Spectrum

NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype

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