Weakly migratory metastatic breast cancer cells activate fibroblasts via microvesicle-Tg2 to facilitate dissemination and metastasis
- Vanderbilt University, United States
- Cornell University, United States
- Vanderbilt University Medical Center, United States
- Hume-Fogg Academic High School, United States
- 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.
Data availability
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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Weakly migratory metastatic breast cancer cells activate fibroblasts via microvesicle-Tg2 to facilitate dissemination and metastasisDryad Digital Repository, doi:10.5061/dryad.4qrfj6qbd.
Article and author information
Author details
Francois Bordeleau
Cynthia A Reinhart-King
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
- Lynne-Marie Postovit, University of Alberta, Canada
Publication history
- Received: October 4, 2021
- Preprint posted: October 29, 2021 (view preprint)
- Accepted: December 5, 2022
- Accepted Manuscript published: December 7, 2022 (version 1)
- 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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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
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