1. Cancer Biology
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Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity

  1. Ophir Shani
  2. Yael Raz
  3. Lea Monteran
  4. Ye'ela Scharff
  5. Oshrat Levi-Galibov
  6. Or Megides
  7. Hila Shacham
  8. Noam Cohen
  9. Dana Silverbush
  10. Camilla Avivi
  11. Roded Sharan
  12. Asaf Madi
  13. Ruth Scherz-Shouval
  14. Iris Barshack
  15. Ilan Tsarfaty
  16. Neta Erez  Is a corresponding author
  1. Tel Aviv University, Israel
  2. The Weizmann Institute of Science, Israel
  3. Sheba Medical Center, Israel
Research Article
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Cite this article as: eLife 2021;10:e60745 doi: 10.7554/eLife.60745

Abstract

Mortality from breast cancer is almost exclusively a result of tumor metastasis, and lungs are one of the main metastatic sites. Cancer-associated fibroblasts (CAFs) are prominent players in the microenvironment of breast cancer. However, their role in the metastatic niche is largely unknown. In this study, we profiled the transcriptional co-evolution of lung fibroblasts isolated from transgenic mice at defined stage-specific time points of metastases formation. Employing multiple knowledge-based platforms of data analysis provided powerful insights on functional and temporal regulation of the transcriptome of fibroblasts. We demonstrate that fibroblasts in lung metastases are transcriptionally dynamic and plastic, and reveal stage-specific gene signatures that imply functional tasks, including extracellular matrix remodeling, stress response and shaping the inflammatory microenvironment. Furthermore, we identified Myc as a central regulator of fibroblast rewiring and found that stromal upregulation of Myc transcriptional networks is associated with disease progression in human breast cancer.

Data availability

Sequencing data have been deposited in GEO under accession code GSE128999.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ophir Shani

    Pathology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Yael Raz

    Pathology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Lea Monteran

    Pathology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Ye'ela Scharff

    Pathology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Oshrat Levi-Galibov

    Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Or Megides

    Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Hila Shacham

    Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Noam Cohen

    Pathology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Dana Silverbush

    Blavatnik School of Computer Sciences, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Camilla Avivi

    Pathology, Sheba Medical Center, Ramat Gan, Israel
    Competing interests
    The authors declare that no competing interests exist.
  11. Roded Sharan

    Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  12. Asaf Madi

    Pathology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  13. Ruth Scherz-Shouval

    Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  14. Iris Barshack

    Pathology, Sheba Medical Center, Ramat Gan, Israel
    Competing interests
    The authors declare that no competing interests exist.
  15. Ilan Tsarfaty

    Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  16. Neta Erez

    Pathology, Tel Aviv University, Tel Aviv, Israel
    For correspondence
    Netaerez@tauex.tau.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6506-9074

Funding

H2020 European Research Council (637069 MetCAF)

  • Ophir Shani
  • Yael Raz

Israel Science Foundation (1060/18)

  • Ophir Shani
  • Yael Raz
  • Noam Cohen
  • Neta Erez

The Emerson Collective

  • Ophir Shani
  • Lea Monteran
  • Neta Erez

Israel Cancer Association

  • Ophir Shani
  • Neta Erez

Israel Cancer Research Fund (Project Grant)

  • Ophir Shani
  • Yael Raz
  • Lea Monteran
  • Neta Erez

Breast Cancer Research Foundation

  • Or Megides
  • Ilan Tsarfaty

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Tel Aviv University. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols #: 01-18-035, M-13-026, 01-17-024) of the Tel Aviv University.

Human subjects: Human patient samples were collected and processed at the Sheba Medical Center, Israel under an approved institutional review board (IRB) (3112-16).

Reviewing Editor

  1. Wilbert Zwart, Netherlands Cancer Institute, Netherlands

Publication history

  1. Received: July 6, 2020
  2. Accepted: June 24, 2021
  3. Accepted Manuscript published: June 25, 2021 (version 1)
  4. Version of Record published: July 5, 2021 (version 2)

Copyright

© 2021, Shani et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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