Abstract
Osteosarcoma (OS) is the most common primary cancer in the skeletal system, characterized by a high incidence of lung metastasis, local recurrence and death. Systemic treatment of this aggressive cancer has not improved significantly since the introduction of chemotherapy regimens, underscoring a critical need for new treatment strategies. TRAIL receptors have long been proposed to be therapeutic targets for cancer treatment, but their role in osteosarcoma remains unclear. In this study, we investigated the expression profile of four TRAIL receptors in human OS cells using total RNA-seq and single-cell RNA-seq (scRNA-seq). The results revealed that TNFRSF10B and TNFRSF10D but not TNFRSF10A and TNFRSF10C are differentially expressed in human OS cells as compared to normal cells. At the single cell level by scRNA-seq analyses, TNFRSF10B, TNFRSF10D, TNFRSF10A and TNFRSF10C are most abundantly expressed in endothelial cells of OS tissues among nine distinct cell clusters. Notably, in osteoblastic OS cells, TNFRSF10B is most abundantly expressed, followed by TNFRSF10D, TNFRSF10A and TNFRSF10C. Similarly, in an OS cell line U2-OS using RNA-seq, TNFRSF10B is most abundantly expressed, followed by TNFRSF10D, TNFRSF10A and TNFRSF10C. According to the TARGET online database, poor patient outcomes were associated with low expression of TNFRSF10C. These results could provide a new perspective to design novel therapeutic targets of TRAIL receptors for the diagnosis, prognosis and treatment of OS and other cancers.