Spectrum of Epithelial-Mesenchymal Transition Phenotypes in Circulating Tumour Cells from Early Breast Cancer Patients

Markiewicz, Aleksandra; Topa, Justyna; Nagel, Anna; Skokowski, Jarosław; Seroczyńska, Barbara; Stokowy, Tomasz; Wełnicka-Jaśkiewicz, Marzena; Żaczek, Anna

doi:10.3390/cancers11010059

Cited by 48 publications

(51 citation statements)

References 68 publications

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“…For instance, one network motif commonly found in core circuits regulating EMT and associated traits is a mutually inhibitory feedback loop between two "master regulators" driving opposing cell phenotypes (Hong et al, 2015;Huang et al, 2015;Saha et al, 2018); for instance, ZEB1 driving EMT and miR-200 driving MET (Jia et al, 2017). An intricate coupling among such feedback loops may give rise to a spectrum of EMT phenotypes as has been seen across cancer types in cell lines, CTCs, and primary tumor biopsies (Armstrong et al, 2011;Huang et al, 2013;Schliekelman et al, 2015;Andriani et al, 2016;Iyer et al, 2019;Markiewicz et al, 2019;Varankar et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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

Chakraborty

George

Tripathi

et al. 2020

Front. Bioeng. Biotechnol.

104

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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Section: Discussionmentioning

confidence: 99%

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

Chakraborty

George

Tripathi

et al. 2020

Front. Bioeng. Biotechnol.

104

106

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show abstract

“…For instance, one network motif commonly found in core circuits regulating EMT and associated traits is a mutually inhibitory feedback loop between two 'master regulators' driving opposing cell phenotypes (Hong et al, 2015;Huang et al, 2015;Saha et al, 2018); for instance, ZEB1 driving EMT and miR-200 driving MET (Jia et al, 2017). An intricate coupling among such feedback loops may give rise to a spectrum of EMT phenotypes as has been seen across cancer types in cell lines, circulating tumor cells and primary tumor biopsies (Armstrong et al, 2011;Huang et al, 2013;Schliekelman et al, 2015;Andriani et al, 2016;Iyer et al, 2019;Markiewicz et al, 2019;Varankar et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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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“…Despite many studies, it is unclear which of those two distinct phenotypes may be prognostic for treatment response, PFS and OS. Some research show that mesenchymal phenotype is associated with poor outcome and shorter PFS [58,[65][66][67], but other studies suggest that prognostic value is rather associated with the epithelial phenotype [40,62]. Interestingly, the presence of mesenchymal CTCs was described a predictive factor, regardless of breast cancer subtype [58].…”

Section: Emt Status In Ctcs and Its Prognostic Valuementioning

confidence: 99%

Circulating Tumor Cells in Early and Advanced Breast Cancer; Biology and Prognostic Value

Fabisiewicz

Szostakowska-Rodzoś

Żaczek

et al. 2020

IJMS

Self Cite

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Breast cancer metastasis is the leading cause of cancer deaths in women and is difficult to combat due to the long periods in which disseminated cells retain a potential to be re-activated and start the relapse. Assessing the number and molecular profile of circulating tumor cells (CTCs) in breast cancer patients, especially in early breast cancer, should help in identifying the possibility of relapse in time for therapeutic intervention to prevent or delay recurrence. While metastatic breast cancer is considered incurable, molecular analysis of CTCs still have a potential to define particular susceptibilities of the cells representing the current tumor burden, which may differ considerably from the cells of the primary tumor, and offer more tailored therapy to the patients. In this review we inspect the routes to metastasis and how they can be linked to specific features of CTCs, how CTC analysis may be used in therapy, and what is the current status of the research and efforts to include CTC analysis in clinical practice.There are two main hypotheses describing cancer dissemination: linear progression, according to which, metastatic potential is gained gradually, and the whole process proceeds in steps and needs time, and parallel progression, according to which dissemination takes place early on, even before clinical manifestation of the tumor [6,7] (Figure 1). In the linear progression model, the evolving primary tumor gives rise to metastases due to increasingly aggressive and invasive phenotypes of the subclones of tumor cells. This model is in agreement with the postulated role of the epithelial-to-mesenchymal transition (EMT) in cancer and assumes active degradation of the stroma and migration into blood vessels by the motile, invasive single cells that broke loose from the epithelial monolayer. In contrast to that, parallel progression postulates intravasation by passive shedding, which may take place shortly after the angiogenic switch, occurring during the early, pre-invasive stage of tumor development [8,9].

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Spectrum of Epithelial-Mesenchymal Transition Phenotypes in Circulating Tumour Cells from Early Breast Cancer Patients

Cited by 48 publications

References 68 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

Circulating Tumor Cells in Early and Advanced Breast Cancer; Biology and Prognostic Value

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