Background Chordoma is a rare mesenchymal malignancy, with a high recurrence rate and unclear tumorigenic mechanism. Genetic alterations, epigenetic regulators, and chromatin spatial organization play crucial roles in the initiation and progression of chordoma. In the current study, we aim to uncover the novel therapeutical targets for chordoma via using integrated multi-omics analysis. Methods The RNA-sequencing (RNA-seq), assay for transposable accessible chromatin by high throughput sequencing (ATAC-seq) and Hi-C were performed between chordoma and human nucleus pulposus (HNP), along with imageological examination and clinical information. The expressions of identified targets were validated by clinical samples and their function were further evaluated by cell and animal experiments via gene knockdown and inhibitors. Results The integrated multi-omics analysis revealed the important roles of bone microenvironment in chordoma tumorigenesis. By comparing the hierarchical structures, CA2 and THNSL2 were identified in the switched compartments, cell-specific boundaries and loops. Additionally, CA2 was highly expressed in chordoma, but barely found in HNP. The cell growth and migration of chordoma cells were dramatically suppressed via inhibition of CA2 either with genetic deletion or pharmaceutical treatment with Dorzolamide HCl. Furthermore, Dorzolamide HCl also regulated the bone microenvironment by blocking the osteoclast differentiation of bone marrow monocytes. Conclusion This study uncovers the roles of bone microenvironment in the chordoma tumorigenesis and identifies CA2 as a novel therapeutic target for chordoma. Besides, our findings suggest Dorzolamide HCl as a promising therapeutic option for chordoma.

BackgroundChordoma is a type of mesenchymal malignancy with a high recurrence rate and poor prognosis. Due to its rarity, the tumorigenic mechanism and optimal therapeutic strategy are not well known.MethodsAll relevant articles of chordoma research from 1 January 2000 to 26 April 2022 were obtained from Web of Science Core Collection database. Blibliometrix was used to acquire basic publication data. Visualization and data table of collaboration network, dynamic analysis, trend topics, thematic map, and factorial analysis were acquired using Blibliometrix package. VOSviewer was used to generate a visualization map of co-citation analysis and co-occurrence.ResultsA total of 2,285 articles related to chordoma were identified. The most influential and productive country/region was the United States, and Capital Medical University has published the most articles. Among all high-impact authors, Adrienne M. Flanagan had the highest average citation rate. Neurosurgery was the important periodical for chordoma research with the highest total/average citation rate. We focused on four hotspots in recent chordoma research. The research on surgical treatment and radiotherapy was relatively mature. The molecular signaling pathway, targeted therapy and immunotherapy for chordoma are not yet mature, which will be the future trends of chordoma research.ConclusionThis study indicates that chordoma studies are increasing. Surgery and radiotherapy are well reported and always play fundamental roles in chordoma treatment. The molecular signaling pathway, targeted therapy, and immunotherapy of chordoma are the latest research hotspots.