Single-Cell Transcriptome Profiling Reveals Intratumoral Heterogeneity in Human Chordomas

Background: Chordoma is a rare and aggressive bone tumor with high recurrence. The intra-tumoral heterogeneity of chordomas is poorly understood, limiting the development of effective therapeutic strategies. Methods: Single-cell RNA sequencing was performed to delineate the transcriptomic landscape of chordomas. Six tumor samples of pathologically classical chordomas were obtained, and 33,737 cells that passed quality control were included in the analysis. Results: The main cellular populations identified with specific markers were: chordomas cells (6392, 47.6%), fibroblasts (6945, 20.6%), mononuclear phagocytes (4734, 14.0%), and T/NK cells (3944, 11.7%). Downstream analysis was performed according to each cellular population. There were six subclusters of chordomas, which exhibited properties of an epithelial-like extracellular matrix, and stem cells with immunosuppression. Although few immune checkpoint was detected on cytotoxic immune cells such as T and NK cells, there was strong immunosuppression exerted by Tregs and M2 macrophages. In addition, the cellular interactions indicated an enhanced TGF-β signaling pathway as the main mechanism for tumor progression, invasion, and immunosuppression in chordomas. Conclusion: Our study contribute to the clarification of intra-tumoral heterogeneity, and may pave the way to identify potential therapeutic targets in chordomas.