The Dynamic Interplay Between Tumor Stromal Discoidin Domain Receptor 2 (DDR2) and Collagen on Neuroblastoma Cellular Mechanics

Cancer development, progression, invasion, metastasis, and responses to therapy rely on a permissive tumor microenvironment. The migration invasion of cancer cells through 3D confined extracellular matrices is coupled with cellular mechanics. Abnormal or dysregulated receptor tyrosine kinase (RTK) signalizing is common within neuroblastoma. Fibrillar collagen RTK discoidin domain receptor 2 (DDR2) is studied in this project as it is presented in both tumor cells and tumor stromal cells, with high DDR2 levels correlated with poor outcomes and metastatic disease. Because DDR2 is upregulated in various cancer cells, we hypothesized that DDR2 binds to collagen within the extracellular matrix (ECM) to promote cellular mechanics during cancer migration. In this work, a comparative study between neuroblastoma cells with normal and down-regulated DDR2 levels is conducted. Downregulated DDR2 cell areas and aspect ratios were significantly decreased when plated on collagen coated substrates. Protrusive speeds were found to be comparable among all cell lines. However, contractile speeds were significantly slower in DDR2 downregulated cells, resulting in decreased detachment of cell edges to participate in migration. Additionally, the depletion of DDR2 was shown to reduce cellular traction forces on collagen coated soft substrates (2kPa), when compared to the control cells. Together, our findings suggests that DDR2 is vital to the role of collagen binding in mediating cellular mechanics and cellular migration in neuroblastoma cells.