Mechanical Confinement and DDR1 Signaling Synergize to Regulate Collagen‐Induced Apoptosis in Rhabdomyosarcoma Cells

Fibrillar collagens promote cell proliferation, migration, and survival in various epithelial cancers and are generally associated with tumor aggressiveness. However, the impact of fibrillar collagens on soft tissue sarcoma behavior remains poorly understood. Unexpectedly, this study finds that fibrillar collagen‐related gene expression is associated with favorable patient prognosis in rhabdomyosarcoma. By developing and using collagen matrices with distinct stiffness and in vivo‐like microarchitectures, this study uncovers that the activation of DDR1 has pro‐apoptotic and of integrin β1 pro‐survival function, specifically in 3D rhabdomyosarcoma cell cultures. It demonstrates that rhabdomyosarcoma cell‐intrinsic or extrinsic matrix remodeling promotes cell survival. Mechanistically, the 3D‐specific collagen‐induced apoptosis results from a dual DDR1‐independent and a synergistic DDR1‐dependent TRPV4‐mediated response to mechanical confinement. Altogether, these results indicate that dense microfibrillar collagen‐rich microenvironments are detrimental to rhabdomyosarcoma cells through an apoptotic response orchestrated by the induction of DDR1 signaling and mechanical confinement. This mechanism helps to explain the preference of rhabdomyosarcoma cells to grow in and metastasize to low fibrillar collagen microenvironments such as the lung. Expression of fibrillar collagen‐related genes is associated with favorable prognosis in rhabdomyosarcoma. Rhabdomyosarcoma cells with low collagen‐remodeling capabilities undergo apoptosis in a collagen microarchitecture and 3‐dimensionality‐dependent manner. Cell apoptosis is caused by the synergy of mechanical confinement and DDR1 activation induced by collagen. Stiffer collagen bundles induce rhabdomyosarcoma cell survival through integrin β1 activation.