IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v573y2019i7774d10.1038_s41586-019-1526-3.html
   My bibliography  Save this article

E-cadherin is required for metastasis in multiple models of breast cancer

Author

Listed:
  • Veena Padmanaban

    (Johns Hopkins University)

  • Ilona Krol

    (University of Basel and University Hospital Basel)

  • Yasir Suhail

    (Johns Hopkins University)

  • Barbara M. Szczerba

    (University of Basel and University Hospital Basel)

  • Nicola Aceto

    (University of Basel and University Hospital Basel)

  • Joel S. Bader

    (Johns Hopkins University)

  • Andrew J. Ewald

    (Johns Hopkins University
    Johns Hopkins University
    Johns Hopkins University)

Abstract

Metastasis is the major driver of death in patients with cancer. Invasion of surrounding tissues and metastasis have been proposed to initiate following loss of the intercellular adhesion protein, E-cadherin1,2, on the basis of inverse correlations between in vitro migration and E-cadherin levels3. However, this hypothesis is inconsistent with the observation that most breast cancers are invasive ductal carcinomas and express E-cadherin in primary tumours and metastases4. To resolve this discrepancy, we tested the genetic requirement for E-cadherin in metastasis using mouse and human models of both luminal and basal invasive ductal carcinomas. Here we show that E-cadherin promotes metastasis in diverse models of invasive ductal carcinomas. While loss of E-cadherin increased invasion, it also reduced cancer cell proliferation and survival, circulating tumour cell number, seeding of cancer cells in distant organs and metastasis outgrowth. Transcriptionally, loss of E-cadherin was associated with upregulation of genes involved in transforming growth factor-β (TGFβ), reactive oxygen species and apoptosis signalling pathways. At the cellular level, disseminating E-cadherin-negative cells exhibited nuclear enrichment of SMAD2/3, oxidative stress and increased apoptosis. Colony formation of E-cadherin-negative cells was rescued by inhibition of TGFβ-receptor signalling, reactive oxygen accumulation or apoptosis. Our results reveal that E-cadherin acts as a survival factor in invasive ductal carcinomas during the detachment, systemic dissemination and seeding phases of metastasis by limiting reactive oxygen-mediated apoptosis. Identifying molecular strategies to inhibit E-cadherin-mediated survival in metastatic breast cancer cells may have potential as a therapeutic approach for breast cancer.

Suggested Citation

  • Veena Padmanaban & Ilona Krol & Yasir Suhail & Barbara M. Szczerba & Nicola Aceto & Joel S. Bader & Andrew J. Ewald, 2019. "E-cadherin is required for metastasis in multiple models of breast cancer," Nature, Nature, vol. 573(7774), pages 439-444, September.
  • Handle: RePEc:nat:nature:v:573:y:2019:i:7774:d:10.1038_s41586-019-1526-3
    DOI: 10.1038/s41586-019-1526-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-019-1526-3
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-019-1526-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Zhoufeng Wang & Zhe Li & Kun Zhou & Chengdi Wang & Lili Jiang & Li Zhang & Ying Yang & Wenxin Luo & Wenliang Qiao & Gang Wang & Yinyun Ni & Shuiping Dai & Tingting Guo & Guiyi Ji & Minjie Xu & Yiying , 2021. "Deciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Weili Wang & Huizhen Zheng & Jun Jiang & Zhi Li & Dongpeng Jiang & Xiangru Shi & Hui Wang & Jie Jiang & Qianqian Xie & Meng Gao & Jianhong Chu & Xiaoming Cai & Tian Xia & Ruibin Li, 2022. "Engineering micro oxygen factories to slow tumour progression via hyperoxic microenvironments," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Jing Wang & Ramon Ocadiz-Ruiz & Matthew S. Hall & Grace G. Bushnell & Sophia M. Orbach & Joseph T. Decker & Ravi M. Raghani & Yining Zhang & Aaron H. Morris & Jacqueline S. Jeruss & Lonnie D. Shea, 2023. "A synthetic metastatic niche reveals antitumor neutrophils drive breast cancer metastatic dormancy in the lungs," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Patrick Aouad & Yueyun Zhang & Fabio Martino & Céline Stibolt & Simak Ali & Giovanna Ambrosini & Sendurai A. Mani & Kelly Maggs & Hazel M. Quinn & George Sflomos & Cathrin Brisken, 2022. "Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Josefine Radke & Elisa Schumann & Julia Onken & Randi Koll & Güliz Acker & Bohdan Bodnar & Carolin Senger & Sascha Tierling & Markus Möbs & Peter Vajkoczy & Anna Vidal & Sandra Högler & Petra Kodajova, 2022. "Decoding molecular programs in melanoma brain metastases," Nature Communications, Nature, vol. 13(1), pages 1-24, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:573:y:2019:i:7774:d:10.1038_s41586-019-1526-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.