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

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.

The Dynamic Relationship of Breast Cancer Cells and Fibroblasts in Fibronectin Accumulation at Primary and Metastatic Tumor Sites

“…We observed that fibroblasts do assemble an ECM network using exogenously supplied proteins, and the matrix network properties are dependent on the source of the FN (Figures 4-6). Past work indicates that cancer-associated fibroblasts are a major effector of ECM production and remodeling in the tumor microenvironment [7]. Fibroblasts, often resident stromal fibroblasts, transition slowly into cancer associated fibroblasts via several mechanisms, including contact signals with BC cells, physiological stress, and soluble factors from the tumor [48].…”

“…In the primary tumor, FN and collagen fibrils accumulate as the tumor develops, which causes an increase in tissue stiffness. This matrix stiffness promotes proliferation, increases tumor cell aggressiveness, and is believed to bolster the number of cancer stem cells [4,7]. Recent research has indicated that FN and collagen fibrils accumulate parallel to the primary tumor border during premetastatic growth.…”

“…Recent research has indicated that FN and collagen fibrils accumulate parallel to the primary tumor border during premetastatic growth. However, in invasive tumors, these fibrils realign perpendicular to the tumor border, acting as "tracks" for tumor cell migration through the basement membrane [7][8][9].…”

Mechanical Cues Affect Migration and Invasion of Cells From Three Different Directions

“…During that interplay, the amount of fibronectin and its degree of fibrillarization within the extracellular matrix are adapted to the specific stage of progress of the disease (Figure 7). In contrast, in invasive cancers, these fibrils reorient themselves vertically to the boundary of the tumor and serve as so-called tracks for the migration of cancer cells across the basement membrane (Yang et al, 2011;Clark and Vignjevic, 2015;Bayer et al, 2019).…”

Meeting report – first discoidin domain receptors meeting

“…Indeed, ablation of DDRs in cancerassociated fibroblasts (CAFs) in the tumour stroma does not affect tumour growth, but prevents from lung metastasis (Corsa et al, 2016). In CAFs, DDR2 controls tumour stiffness by reorganizing the collagen fibres, thereby facilitating integrin activation at the tumour-stromal boundary and favouring cell invasion (Bayer et al, 2019). Serge Roche (CRBM, Montpellier, France) provided evidence for the therapeutic benefit of targeting DDR1 in colorectal cancer (CRC) cells.…”