Mechanical confinement and DDR1 signalling synergise to regulate collagen-induced apoptosis in rhabdomyosarcoma cells

Abstract

Fibrillar collagens promote cell proliferation, migration, and survival in various epithelial cancers and are generally associated with tumour aggressiveness. However, the impact of fibrillar collagens on soft tissue sarcoma behaviour remains poorly understood.Unexpectedly, we find here that fibrillar collagen-related gene expression is associated with favourable patient prognosis in rhabdomyosarcoma. By developing and using collagen matrices with distinct stiffness and in vivo-like microarchitectures, we uncover that the activation of DDR1 has pro-apoptotic and integrin β1 pro-survival function, specifically in 3D rhabdomyosarcoma cell cultures. We demonstrate that rhabdomyosarcoma cell-intrinsic or extrinsic matrix remodelling promotes cell survival. Mechanistically, we find that the 3D-specific collagen-induced apoptosis results from a dual DDR1-independent and a synergistic DDR1-dependent TRPV4-mediated response to mechanical confinement. Altogether, our results indicate that dense microfibrillar collagen-rich microenvironments are detrimental to rhabdomyosarcoma cells through an apoptotic response orchestrated by the induction of DDR1 signalling and mechanical confinement. This mechanism helps to explain the preference of rhabdomyosarcoma cells to grow in and metastasise to low fibrillar collagen microenvironments such as the lung.

Assessment of Stiffness-Dependent Autophagosome Formation and Apoptosis in Embryonal Rhabdomyosarcoma Tumor Cells

“…The increased stiffness of the tumor tissue limits tumor growth but enhances tumor aggressiveness. Through the enzymatic ECM remodeling and degradation, cells can be free from physical barriers favoring tumor growth and invasion, which is a common feature of most cancers (3).…”