The Role of Discoidin Domain Receptor 2 (DDR2) and Collagen on Neuroblastoma Cellular Mechanosensing

Increased extracellular matrix (ECM) stiffness is a characteristic commonly observed in tumors. Cancer cells can sense changes in substrate stiffness and adjust their migration, proliferation, and differentiation accordingly. Cell-ECM adhesion is crucial for cells to sense substrate stiffness. Discoidin Domain Receptor 2 (DDR2) is a collagen receptor and has been shown to play a role cell-ECM adhesion. Elevated levels of DDR2 in tumor cells have been associated with unfavorable outcomes and metastatic disease. In this study, we aim to investigate the significance of DDR2-collagen interaction in substrate stiffness sensing by studying how DDR2 downregulation affects the responses of SHY5Y cells, a neuroblastoma cell line that expresses DDR2, to substrate stiffness changes. Cells were cultured on collagen-coated polyacrylamide gels with stiffness ranging from 800 Pa to 20 kPa. On stiffer substrates, we observed cells with larger spreading area, more polarized shape, stronger traction force, greater cytoskeletal stiffness, and upregulated neuroblastoma-associated gene expression. These suggest that SHY5Y cells are sensitive to sense ECM stiffness. In contrast, the sh-DDR2 SHY5Ycell line, in which DDR2 expression was downregulated by sh-RNA mediated depletion, did not demonstrate substrate stiffness sensitivity. Our results indicate that DDR2 plays an important role in cellular substrate stiffness sensing. This highlights the potential significance of DDR2 as a target for cancer treatment, as modulation of DDR2-collagen interactions could potentially impact cancer cell behavior and invasion.