Integrative Transcriptomic Analysis Reveals a Multiphasic Epithelial–Mesenchymal Spectrum in Cancer and Non-tumorigenic Cells
Epithelial–mesenchymal transition (EMT), the conversion between rigid epithelial cells and motile mesenchymal cells, is a reversible cellular process involved in tumorigenesis, metastasis, and chemoresistance. Numerous studies have found that several types of tumor cells show a high degree of cell-t...
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doaj-e8881b9d91ed4ea49c5caf3744930f9d2020-11-25T00:11:20ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-01-01910.3389/fonc.2019.01479504072Integrative Transcriptomic Analysis Reveals a Multiphasic Epithelial–Mesenchymal Spectrum in Cancer and Non-tumorigenic CellsNicholas Panchy0Nicholas Panchy1Cassandra Azeredo-Tseng2Cassandra Azeredo-Tseng3Michael Luo4Natalie Randall5Tian Hong6Tian Hong7Department of Biochemistry & Cellular and Molecular Biology, The University of Tennessee, Knoxville, Knoxville, TN, United StatesNational Institute for Mathematical and Biological Synthesis, Knoxville, TN, United StatesDepartment of Biochemistry, New College of Florida, Sarasota, FL, United StatesDepartment of Applied Mathematics, New College of Florida, Sarasota, FL, United StatesDepartment of Mathematics & Statistics, The College of New Jersey, Ewing Township, NJ, United StatesDepartment of Mathematics and Computer Science, Austin College, Sherman, TX, United StatesDepartment of Biochemistry & Cellular and Molecular Biology, The University of Tennessee, Knoxville, Knoxville, TN, United StatesNational Institute for Mathematical and Biological Synthesis, Knoxville, TN, United StatesEpithelial–mesenchymal transition (EMT), the conversion between rigid epithelial cells and motile mesenchymal cells, is a reversible cellular process involved in tumorigenesis, metastasis, and chemoresistance. Numerous studies have found that several types of tumor cells show a high degree of cell-to-cell heterogeneity in terms of their gene expression signatures and cellular phenotypes related to EMT. Recently, the prevalence and importance of partial or intermediate EMT states have been reported. It is unclear, however, whether there is a general pattern of cancer cell distribution in terms of the overall expression of epithelial-related genes and mesenchymal-related genes, and how this distribution is related to EMT process in normal cells. In this study, we performed integrative transcriptomic analysis that combines cancer cell transcriptomes, time course data of EMT in non-tumorigenic epithelial cells, and epithelial cells with perturbations of key EMT factors. Our statistical analysis shows that cancer cells are widely distributed in the EMT spectrum, and the majority of these cells can be described by an EMT path that connects the epithelial and the mesenchymal states via a hybrid expression region in which both epithelial genes and mesenchymal genes are highly expressed overall. We found that key patterns of this EMT path are observed in EMT progression in non-tumorigenic cells and that transcription factor ZEB1 plays a key role in defining this EMT path via diverse gene regulatory circuits connecting to epithelial genes. We performed Gene Set Variation Analysis to show that the cancer cells at hybrid EMT states also possess hybrid cellular phenotypes with both high migratory and high proliferative potentials. Our results reveal critical patterns of cancer cells in the EMT spectrum and their relationship to the EMT process in normal cells, and provide insights into the mechanistic basis of cancer cell heterogeneity and plasticity.https://www.frontiersin.org/article/10.3389/fonc.2019.01479/fullhybrid EMT statesZEB1breast cancercell migration and proliferationtumor cell heterogeneity |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nicholas Panchy Nicholas Panchy Cassandra Azeredo-Tseng Cassandra Azeredo-Tseng Michael Luo Natalie Randall Tian Hong Tian Hong |
spellingShingle |
Nicholas Panchy Nicholas Panchy Cassandra Azeredo-Tseng Cassandra Azeredo-Tseng Michael Luo Natalie Randall Tian Hong Tian Hong Integrative Transcriptomic Analysis Reveals a Multiphasic Epithelial–Mesenchymal Spectrum in Cancer and Non-tumorigenic Cells Frontiers in Oncology hybrid EMT states ZEB1 breast cancer cell migration and proliferation tumor cell heterogeneity |
author_facet |
Nicholas Panchy Nicholas Panchy Cassandra Azeredo-Tseng Cassandra Azeredo-Tseng Michael Luo Natalie Randall Tian Hong Tian Hong |
author_sort |
Nicholas Panchy |
title |
Integrative Transcriptomic Analysis Reveals a Multiphasic Epithelial–Mesenchymal Spectrum in Cancer and Non-tumorigenic Cells |
title_short |
Integrative Transcriptomic Analysis Reveals a Multiphasic Epithelial–Mesenchymal Spectrum in Cancer and Non-tumorigenic Cells |
title_full |
Integrative Transcriptomic Analysis Reveals a Multiphasic Epithelial–Mesenchymal Spectrum in Cancer and Non-tumorigenic Cells |
title_fullStr |
Integrative Transcriptomic Analysis Reveals a Multiphasic Epithelial–Mesenchymal Spectrum in Cancer and Non-tumorigenic Cells |
title_full_unstemmed |
Integrative Transcriptomic Analysis Reveals a Multiphasic Epithelial–Mesenchymal Spectrum in Cancer and Non-tumorigenic Cells |
title_sort |
integrative transcriptomic analysis reveals a multiphasic epithelial–mesenchymal spectrum in cancer and non-tumorigenic cells |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2020-01-01 |
description |
Epithelial–mesenchymal transition (EMT), the conversion between rigid epithelial cells and motile mesenchymal cells, is a reversible cellular process involved in tumorigenesis, metastasis, and chemoresistance. Numerous studies have found that several types of tumor cells show a high degree of cell-to-cell heterogeneity in terms of their gene expression signatures and cellular phenotypes related to EMT. Recently, the prevalence and importance of partial or intermediate EMT states have been reported. It is unclear, however, whether there is a general pattern of cancer cell distribution in terms of the overall expression of epithelial-related genes and mesenchymal-related genes, and how this distribution is related to EMT process in normal cells. In this study, we performed integrative transcriptomic analysis that combines cancer cell transcriptomes, time course data of EMT in non-tumorigenic epithelial cells, and epithelial cells with perturbations of key EMT factors. Our statistical analysis shows that cancer cells are widely distributed in the EMT spectrum, and the majority of these cells can be described by an EMT path that connects the epithelial and the mesenchymal states via a hybrid expression region in which both epithelial genes and mesenchymal genes are highly expressed overall. We found that key patterns of this EMT path are observed in EMT progression in non-tumorigenic cells and that transcription factor ZEB1 plays a key role in defining this EMT path via diverse gene regulatory circuits connecting to epithelial genes. We performed Gene Set Variation Analysis to show that the cancer cells at hybrid EMT states also possess hybrid cellular phenotypes with both high migratory and high proliferative potentials. Our results reveal critical patterns of cancer cells in the EMT spectrum and their relationship to the EMT process in normal cells, and provide insights into the mechanistic basis of cancer cell heterogeneity and plasticity. |
topic |
hybrid EMT states ZEB1 breast cancer cell migration and proliferation tumor cell heterogeneity |
url |
https://www.frontiersin.org/article/10.3389/fonc.2019.01479/full |
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