DDR2 controls breast tumor stiffness and metastasis by regulating Integrin mediated mechanotransduction in CAFs
- Washington University in St Louis, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Gregory D Longmore
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.
Reviewing Editor
- Joan Massagué, Memorial Sloan-Kettering Cancer Center, United States
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.
Version history
- Received: January 24, 2019
- Accepted: May 29, 2019
- Accepted Manuscript published: May 30, 2019 (version 1)
- 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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DDR2 controls breast tumor stiffness and metastasis by regulating Integrin mediated mechanotransduction in CAFs
eLife 8:e45508.
https://doi.org/10.7554/eLife.45508
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