A Mechanism for Epithelial-Mesenchymal Heterogeneity in a Population of Cancer Cells

Tripathi, Shubham; Levine, Herbert; Jolly, Mohit Kumar

doi:10.1101/592691

Cited by 65 publications

(77 citation statements)

References 64 publications

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“…The observations about sarcomas, breast cancer, and non-small cell lung cancer are well-supported by existing experimental data (Blick et al, 2008;Schliekelman et al, 2015;Jolly et al, 2019b); however, the predictions about other cancer types identified to be more heterogeneous need further investigation. Our results also demonstrate a link between the predominance of hybrid E/M status and heterogeneity patterns, possibly emerging due to relatively higher plasticity of cells in one or more hybrid E/M phenotypes (Pastushenko et al, 2018;Tripathi et al, 2019b). These observations also imply that tumor types with a greater number of hybrid E/M cells may require alternative treatment strategies as compared to those containing predominantly epithelial or predominantly mesenchymal populations.…”

Section: Discussionsupporting

confidence: 62%

“…the proclivity of individual cells in a population to obtain and switch among multiple phenotypic states. Such plasticity is typically seen to be higher in cells in one or more hybrid E/M states (Pastushenko and Blanpain, 2019;Tripathi et al, 2019bTripathi et al, , 2019a. Thus, we asked whether the frequency of hybrid E/M phenotype contributes to heterogeneity in terms of EMT scoring.…”

Section: Variability In Emt Scores Measures Tumor Heterogeneitymentioning

confidence: 99%

“…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). Consequently, the presence and frequency of such hybrid E/M cells in primary tumors and in circulating tumor cells (CTCs) can be associated with poor patient survival (Jolly et al, 2019a;Saxena et al, 2019).…”

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: Discussionsupporting

confidence: 62%

Section: Variability In Emt Scores Measures Tumor Heterogeneitymentioning

confidence: 99%

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

Self Cite

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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). These preclinical experimental observations are supported by clinical analysis of carcinoma samples suggesting that the presence of hybrid E/M cells in a patient at the time of diagnosis associates with poor patient outcomes.…”

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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“…These hybrid E/M phenotypes may drive collective cell migration as clusters of tumor cells (CTCs) and can be more aggressive than cells in pure epithelial or mesenchymal phenotypes [2]. Importantly, tumor cells may switch among different phenotypes -E, M and hybrid E/M [3][4][5]. Such dynamic and reversible switching can help tumor cells to overcome various challenges during disease progression such as anoikis [6], and assaults by the immune system [7].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

Jia

Tripathi

Chakraborty

et al. 2020

Preprint

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Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

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A Mechanism for Epithelial-Mesenchymal Heterogeneity in a Population of Cancer Cells

Cited by 65 publications

References 64 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

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

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

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