Weakly migratory metastatic breast cancer cells activate fibroblasts via microvesicle-Tg2 to facilitate dissemination and metastasis

  1. Samantha C Schwager
  2. Katherine Young
  3. Lauren A Hapach
  4. Caroline M Carlson
  5. Jenna A Mosier
  6. Tanner J McArdle
  7. Wenjun Wang
  8. Curtis Schunk
  9. Anissa L Jayathilake
  10. Madison E Bates
  11. Francois Bordeleau
  12. Marc A Antonyak
  13. Richard A Cerione
  14. Cynthia A Reinhart-King  Is a corresponding author
  1. Vanderbilt University, United States
  2. Cornell University, United States
  3. Vanderbilt University Medical Center, United States
  4. Hume-Fogg Academic High School, United States
  5. Université Laval, Canada

Abstract

Cancer cell migration is highly heterogeneous, and the migratory capability of cancer cells is thought to be an indicator of metastatic potential. It is becoming clear that a cancer cell does not have to be inherently migratory to metastasize, with weakly migratory cancer cells often found to be highly metastatic. However, the mechanism through which weakly migratory cells escape from the primary tumor remains unclear. Here, utilizing phenotypically sorted highly and weakly migratory human breast cancer cells, we demonstrate that weakly migratory metastatic cells disseminate from the primary tumor via communication with stromal cells. While highly migratory cells are capable of single cell migration, weakly migratory cells rely on cell-cell signaling with fibroblasts to escape the primary tumor. Weakly migratory cells release microvesicles rich in tissue transglutaminase 2 (Tg2) which activate murine fibroblasts and lead weakly migratory cancer cell migration in vitro. These microvesicles also induce tumor stiffening and fibroblast activation in vivo and enhance the metastasis of weakly migratory cells. Our results identify microvesicles and Tg2 as potential therapeutic targets for metastasis and reveal a novel aspect of the metastatic cascade in which weakly migratory cells release microvesicles which activate fibroblasts to enhance cancer cell dissemination.

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Source data is included in supporting files. All supporting data sheets contain the figures in the file name and the figure panel in the excel tab.

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Article and author information

Author details

  1. Samantha C Schwager

    Department of Biomedical Engineering, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Katherine Young

    Department of Biomedical Engineering, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Lauren A Hapach

    Department of Biomedical Engineering, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Caroline M Carlson

    Department of Biomedical Engineering, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jenna A Mosier

    Department of Biomedical Engineering, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tanner J McArdle

    Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Wenjun Wang

    Department of Biomedical Engineering, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0907-6282
  8. Curtis Schunk

    Department of Biomedical Engineering, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Anissa L Jayathilake

    Hume-Fogg Academic High School, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Madison E Bates

    Department of Biomedical Engineering, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Francois Bordeleau

    Faculty of Medicine, Université Laval, Québecc, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5114-1757
  12. Marc A Antonyak

    Department of Biomedical Science, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Richard A Cerione

    Department of Biomedical Science, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Cynthia A Reinhart-King

    1Department of Biomedical Engineering, Vanderbilt University, Nashville, United States
    For correspondence
    Cynthia.Reinhart-King@vanderbilt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6959-3914

Funding

W. M. Keck Foundation

  • Cynthia A Reinhart-King

National Institute of General Medical Sciences (GM13117)

  • Cynthia A Reinhart-King

National Science Foundation (1937963)

  • Samantha C Schwager
  • Jenna A Mosier

National Science Foundation (DGE-1650441)

  • Lauren A Hapach

Cancer Research Society

  • Francois Bordeleau

National Cancer Institute (K99CA212270)

  • Francois Bordeleau

National Cancer Institute (5P30 CA68485-19)

  • Cynthia A Reinhart-King

National Institute of Diabetes and Digestive and Kidney Diseases (U24 DK059637-16)

  • Cynthia A Reinhart-King

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

Ethics

Animal experimentation: Experiments were performed in accordance with AAALAC guidelines and were approved by the Vanderbilt University Institutional Animal Care and Use Committee (Protocol No. M1700029-00).

Reviewing Editor

  1. Lynne-Marie Postovit, University of Alberta, Canada

Version history

  1. Received: October 4, 2021
  2. Preprint posted: October 29, 2021 (view preprint)
  3. Accepted: December 5, 2022
  4. Accepted Manuscript published: December 7, 2022 (version 1)
  5. Version of Record published: December 20, 2022 (version 2)

Copyright

© 2022, Schwager 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 C Schwager
  2. Katherine Young
  3. Lauren A Hapach
  4. Caroline M Carlson
  5. Jenna A Mosier
  6. Tanner J McArdle
  7. Wenjun Wang
  8. Curtis Schunk
  9. Anissa L Jayathilake
  10. Madison E Bates
  11. Francois Bordeleau
  12. Marc A Antonyak
  13. Richard A Cerione
  14. Cynthia A Reinhart-King
(2022)
Weakly migratory metastatic breast cancer cells activate fibroblasts via microvesicle-Tg2 to facilitate dissemination and metastasis
eLife 11:e74433.
https://doi.org/10.7554/eLife.74433

Share this article

https://doi.org/10.7554/eLife.74433

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