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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
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    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.

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