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  • DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs.

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

eLife (2019-05-31)
Samantha Vh Bayer, Whitney R Grither, Audrey Brenot, Priscilla Y Hwang, Craig E Barcus, Melanie Ernst, Patrick Pence, Christopher Walter, Amit Pathak, Gregory D Longmore
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-15, ascites fluid
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Monoclonal Anti-Vinculin antibody produced in mouse, clone hVIN-1, ascites fluid
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Monoclonal Anti-Actin, α-Smooth Muscle, clone 1A4, ascites fluid
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Anti-Mouse Collagen Type I Antibody, Chemicon®, from rabbit
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Anti-Fibroblast activation protein alpha (FAP) Antibody, from rabbit
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Rap1 Activation Assay Kit, Non-radioactive Rap1 Activation Assay Kit that uses Ral GDS RBD, agarose (Catalog # 14-455) to precipitate Rap1-GTP from cell lysates & detection by a Rap1 specific antibody.
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Monoclonal Anti-Talin antibody produced in mouse, clone 8d4, ascites fluid
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Monoclonal Anti-β-Tubulin antibody produced in mouse, clone TUB 2.1, ascites fluid