Context-dependent EMT programs in cancer metastasis

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In this review, Aiello and Kang discuss the molecular mechanisms, regulatory networks, and functional consequences of epithelial–mesenchymal transition (EMT) in the context of cancer metastasis, with a particular focus on partial EMT and cellular plasticity.

Abstract

Epithelial–mesenchymal transition (EMT) is a developmental process whereby stationary, adherent cells acquire the ability to migrate. EMT is critical for dramatic cellular movements during embryogenesis; however, tumor cells can reactivate EMT programs, which increases their aggressiveness. In addition to motility, EMT is associated with enhanced stem cell properties and drug resistance; thus it can drive metastasis, tumor recurrence, and therapy resistance in the context of cancer. However, the precise requirements for EMT in metastasis have not been fully delineated, with different tumor types relying on discrete EMT effectors. Most tumor cells do not undergo a full EMT, but rather adopt some qualities of mesenchymal cells and maintain some epithelial characteristics. Emerging evidence suggests that partial EMT can drive distinct migratory properties and enhance the epithelial-mesenchymal plasticity of cancer cells as well as cell fate plasticity. This review discusses the diverse regulatory mechanisms and functional consequences of EMT, with an emphasis on the importance of partial EMT.

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The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion.

Joke Comijn, Geert Berx, Petra Vermassen … (2001)

Transcriptional downregulation of E-cadherin appears to be an important event in the progression of various epithelial tumors. SIP1 (ZEB-2) is a Smad-interacting, multi-zinc finger protein that shows specific DNA binding activity. Here, we report that expression of wild-type but not of mutated SIP1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadherin promoter. SIP1 and Snail bind to partly overlapping promoter sequences and showed similar silencing effects. SIP1 can be induced by TGF-beta treatment and shows high expression in several E-cadherin-negative human carcinoma cell lines. Conditional expression of SIP1 in E-cadherin-positive MDCK cells abrogates E-cadherin-mediated intercellular adhesion and simultaneously induces invasion. SIP1 therefore appears to be a promoter of invasion in malignant epithelial tumors.

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Matrix stiffness drives Epithelial-Mesenchymal Transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway

Spencer Wei, Laurent Fattet, Jeff H. Tsai … (2015)

Matrix stiffness potently regulates cellular behavior in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased matrix stiffness and correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechano-mediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing matrix stiffness. High matrix stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fiber alignment, a marker of increasing matrix stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion, and metastasis.

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Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients

Bahriye Aktas, Mitra Tewes, Tanja Fehm … (2009)

Introduction The persistence of circulating tumor cells (CTC) in breast cancer patients might be associated with stem cell like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, these cells also may undergo phenotypic changes, known as epithelial-mesenchymal transition (EMT), which allows them to travel to the site of metastasis formation without getting affected by conventional treatment. Here we evaluated 226 blood samples of 39 metastatic breast cancer patients during a follow-up of palliative chemo-, antibody – or hormonal therapy for the expression of the stem cell marker ALDH1 and markers for EMT and correlated these findings with the presence of CTC and response to therapy. Methods 2 × 5 ml blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1 and HER2 transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [Twist1, Akt2, PI3Kα] and separately for the tumor stem-cell markers ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample. Results 97% of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts. CTC were detected in 69/226 (31%) cancer samples. In the CTC (+) group, 62% were positive for at least one of the EMT markers and 69% for ALDH1, respectively. In the CTC (-) group the percentages were 7% and 14%, respectively. In non-responders, EMT and ALDH1 expression was found in 62% and 44% of patients, in responders the rates were 10% and 5%, respectively. Conclusions Our data indicate that a major proportion of CTC of metastatic breast cancer patients shows EMT and tumor stem cell characteristics. Further studies are needed to prove whether these markers might serve as an indicator for therapy resistant tumor cell populations and, therefore, an inferior prognosis.

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Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J. Exp. Med

Journal ID (publisher-id): jem

Journal ID (hwp): jem

Title: The Journal of Experimental Medicine

Publisher: Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date (Print): 06 May 2019

Publication date (Electronic): 11 April 2019

Volume: 216

Issue: 5

Pages: 1016-1026

Affiliations

[1]Department of Molecular Biology, Princeton University, Princeton, NJ

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Correspondence to Yibin Kang: ykang@ 123456princeton.edu

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Yibin Kang http://orcid.org/0000-0002-1626-6730

Article

Publisher ID: 20181827

DOI: 10.1084/jem.20181827

PMC ID: 6504222

PubMed ID: 30975895

SO-VID: 0ec18de6-fc0b-4ffc-bdb5-af9198a70935

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This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

History

Date received : 19 February 2019

Date revision received : 22 March 2019

Date accepted : 22 March 2019

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Pages: 11

Funding

Funded by: Brewster Foundation, DOI https://doi.org/10.13039/100008150;

Funded by: Breast Cancer Research Foundation, DOI https://doi.org/10.13039/100001006;

Funded by: Susan G. Komen Foundation, DOI https://doi.org/10.13039/100009634;

Funded by: US Department of Defense, DOI https://doi.org/10.13039/100000005;

Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;

Funded by: US Department of Defense, DOI https://doi.org/10.13039/100000005;

Award ID: BC170055

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Context-dependent EMT programs in cancer metastasis

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Most cited references 66

The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion.

Matrix stiffness drives Epithelial-Mesenchymal Transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway

Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients

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