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      Intermediate cell states in epithelial-to-mesenchymal transition

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          Abstract

          The transition of epithelial cells into a mesenchymal state (epithelial-to-mesenchymal transition or EMT) is a highly dynamic process implicated in various biological processes. During EMT, cells do not necessarily exist in ‘pure’ epithelial or mesenchymal states. There are cells with mixed (or hybrid) features of the two, which are termed as the intermediate cell states (ICSs). While the exact functions of ICS remain elusive, together with EMT it appears to play important roles in embryogenesis, tissue development, and pathological processes such as cancer metastasis. Recent single cell experiments and advanced mathematical modeling have improved our capability in identifying ICS and provided a better understanding of ICS in development and disease. Here, we review the recent findings related to the ICS in/or EMT and highlight the challenges in the identification and functional characterization of ICS.

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          Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression

          Douglas Micalizzi, Susan M. Farabaugh, Heide Ford (2010)
          From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-β and Wnt/β-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer.
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            An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530)

            R Huang, Julia Wong, T Tan … (2013)
            The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial–mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial–mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.
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              Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

              Brian Bierie, Sarah Pierce, Cornelia Kroeger … (2017)
              It is widely appreciated that carcinoma cells exhibiting certain mesenchymal traits are enriched for cancer stem cells (CSCs) and can give rise to tumors with aggressive features. Whereas it has been proposed that mesenchymal carcinoma cell populations are internally heterogeneous, the field has made little progress in resolving the specific subtypes of mesenchymal carcinoma cells that pose the greatest risk for patients. We demonstrate the utility of integrin-β4 (ITGB4) in segregating these cells into distinct subpopulations with differing tumor-initiating abilities and pathological behaviors. In addition, we identified mechanistic links between ZEB1 (zinc finger E-box binding homeobox 1) and TAp63α (tumor protein 63 isoform 1) as regulators of ITGB4 expression and demonstrate that ITGB4 can be used as a marker to determine which patients are more likely to relapse after treatment. Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin-β4 (ITGB4), can be used to enable stratification of mesenchymal-like triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4 + cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival. Mechanistically, we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101197454
                Journal ID (pubmed-jr-id): 32542
                Journal ID (nlm-ta): Phys Biol
                Journal ID (iso-abbrev): Phys Biol
                Title: Physical biology
                ISSN (Print): 1478-3967
                ISSN (Electronic): 1478-3975
                Publication date Nihms-submitted: 26 June 2019
                Publication date (Electronic): 18 January 2019
                Publication date Collection: 18 January 2019
                Publication date PMC-release: 01 July 2019
                Volume: 16
                Issue: 2
                Page: 021001
                Affiliations
                [1 ]Department of Mathematics, University of California, Irvine, CA 92697, United States of America
                [2 ]Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, United States of America
                [3 ]Department of Mathematics, University of Nebraska-Lincoln, Lincoln, NE 68588, United States of America
                [4 ]Department of Development and Cell Biology, University of California, Irvine, CA 92697, United States of America
                [5 ]Co-first authors.
                Author notes
                [6 ]Authors to whom any correspondence should be addressed. xdai@ 123456uci.edu and qnie@ 123456uci.edu
                Author information
                http://orcid.org/0000-0002-8804-3368
                Article
                Manuscript ID: NIHMS1034880
                DOI: 10.1088/1478-3975/aaf928
                PMC ID: 6602058
                PubMed ID: 30560804
                SO-VID: 278b06eb-8f3a-45f5-ab3b-a48f2f24b5bb
                License:

                Original content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI.

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                Subject: Article

                Keywords: emt,metastasis,stemness
                Data availability:
                Keywords: emt, metastasis, stemness

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