1. DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs
- Author
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Whitney R. Grither, Christopher Walter, Amit Pathak, Samantha Van Hove Bayer, Melanie Ernst, Gregory D. Longmore, Audrey Brenot, Craig E. Barcus, Patrick Pence, and Priscilla Y. Hwang
- Subjects
collagen ,0301 basic medicine ,Integrins ,Mouse ,QH301-705.5 ,Science ,Integrin ,Breast Neoplasms ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,Collagen receptor ,Mice ,03 medical and health sciences ,Discoidin Domain Receptor 2 ,0302 clinical medicine ,Cancer-Associated Fibroblasts ,In vivo ,Tumor Microenvironment ,medicine ,Animals ,Humans ,DDR2 ,metastasis ,Biology (General) ,Neoplasm Metastasis ,Mechanotransduction ,Cancer Biology ,mechanotransduction ,Tumor microenvironment ,Lung ,General Immunology and Microbiology ,biology ,business.industry ,General Neuroscience ,Cell Biology ,General Medicine ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Tumor progression ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Medicine ,business ,Research Article - 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.
- Published
- 2019