DDR2 controls breast tumor stiffness and metastasis by regulating Integrin mediated mechanotransduction in CAFs

Abstract

Biomechanical changes in the tumor microenvironment influence tumor progression and metastases. Collagen content and fiber organization within the tumor stroma are major contributors to biomechanical changes (e., tumor stiffness) and correlated with tumor aggressiveness and outcome. What signals and in what cells control collagen organization within the tumors, and how, is not fully understood. We show in mouse breast tumors that the action of the collagen receptor DDR2 in CAFs controls tumor stiffness by reorganizing collagen fibers specifically at the tumor-stromal boundary. These changes were associated with lung metastases. The action of DDR2 in mouse and human CAFs, and tumors in vivo, was found to influence mechanotransduction by controlling full collagen-binding integrin activation via Rap1-mediated Talin1 and Kindlin2 recruitment. The action of DDR2 in tumor CAFs is thus critical for remodeling collagen fibers at the tumor-stromal boundary to generate a physically permissive tumor microenvironment for tumor cell invasion and metastases.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

  1. Samantha VH Bayer

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Whitney R Grither

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Audrey Brenot

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Priscilla Y Hwang

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Craig E Barcus

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Melanie Ernst

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8995-3507
  7. Patrick Pence

    ICCE Institute, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Christopher Walter

    Department of Mechanical Engineering, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Amit Pathak

    Department of Mechanical Engineering, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Gregory D Longmore

    ICCE Institute, Washington University in St Louis, St Louis, United States
    For correspondence
    glongmore@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7568-8151

Funding

National Institute for Health Research (R01 CA196205)

  • Gregory D Longmore

National Institute for Health Research (R01 CA223758)

  • Gregory D Longmore

National Institute for Health Research (U54 CA210173)

  • Gregory D Longmore

American Cancer Society (131342-PF-17-238-01-CSM)

  • Priscilla Y Hwang

National Institute for Health Research (F30 CA200386)

  • Samantha VH Bayer

National Institute for Health Research (T32 GM07200)

  • Samantha VH Bayer
  • Whitney R Grither

National Institute for Health Research (T32 CA113275)

  • Craig E Barcus

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 National Institutes of Health under protocol #20150145.

Reviewing Editor

  1. Joan Massagué, Memorial Sloan-Kettering Cancer Center, United States

Version history

  1. Received: January 24, 2019
  2. Accepted: May 29, 2019
  3. Accepted Manuscript published: May 30, 2019 (version 1)
  4. Version of Record published: June 7, 2019 (version 2)

Copyright

© 2019, Bayer 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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  1. Samantha VH Bayer
  2. Whitney R Grither
  3. Audrey Brenot
  4. Priscilla Y Hwang
  5. Craig E Barcus
  6. Melanie Ernst
  7. Patrick Pence
  8. Christopher Walter
  9. Amit Pathak
  10. Gregory D Longmore
(2019)
DDR2 controls breast tumor stiffness and metastasis by regulating Integrin mediated mechanotransduction in CAFs
eLife 8:e45508.
https://doi.org/10.7554/eLife.45508

Share this article

https://doi.org/10.7554/eLife.45508

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