DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs
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
Affiliations
Samantha VH Bayer
ICCE Institute, Washington University, St Louis, United States; Department of Cell Biology and Physiology, Washington University, St Louis, United States; Department of Medicine, Washington University, St Louis, United States
Whitney R Grither
ICCE Institute, Washington University, St Louis, United States; Department of Medicine, Washington University, St Louis, United States; Department of Biochemistry, Washington University, St Louis, United States
Audrey Brenot
ICCE Institute, Washington University, St Louis, United States; Department of Medicine, Washington University, St Louis, United States
Priscilla Y Hwang
ICCE Institute, Washington University, St Louis, United States; Department of Medicine, Washington University, St Louis, United States
Craig E Barcus
ICCE Institute, Washington University, St Louis, United States; Department of Medicine, Washington University, St Louis, United States
ICCE Institute, Washington University, St Louis, United States; Department of Cell Biology and Physiology, Washington University, St Louis, United States; Department of Medicine, Washington University, St Louis, United States
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.
