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Updated: Oct 30, 2025
Dissection of Local Ca2+ Signals in Cultured Cells by Membrane-targeted Ca2+ Indicators
Published on: March 22, 2019
A comparative integrated multi-omics analysis identifies CA2 as a novel target for chordoma
Tong Meng1,2, Runzhi Huang3, Jiali Jin2
1Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
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 functions 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 (carbonic anhydrase II) and THNSL2 (threonine synthase-like 2) 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.
Insights
This study reveals the bone microenvironment
Area of Science:
- Oncology
- Genomics
- Epigenetics
Background:
- Chordoma is a rare, recurrent mesenchymal malignancy with poorly understood tumorigenesis.
- Genetic, epigenetic, and chromatin organization factors are implicated in chordoma development.
- There is a need for novel therapeutic targets in chordoma treatment.
Purpose of the Study:
- To identify novel therapeutic targets for chordoma using integrated multi-omics analysis.
- To investigate the role of the bone microenvironment in chordoma tumorigenesis.
Main Methods:
- Integrated multi-omics analysis including RNA-sequencing (RNA-seq), ATAC-seq, and Hi-C.
- Comparison between chordoma and human nucleus pulposus (HNP) tissues.
- Validation of target gene expression in clinical samples and functional evaluation in cell and animal models.
Main Results:
- The bone microenvironment plays a significant role in chordoma tumorigenesis.
- Carbonic anhydrase II (CA2) and THNSL2 were identified as key genes involved in chordoma.
- CA2 is highly expressed in chordoma and its inhibition (using Dorzolamide HCl) suppressed tumor cell growth and migration.
- Dorzolamide HCl also impacted the bone microenvironment by inhibiting osteoclast differentiation.
Conclusions:
- The bone microenvironment is crucial in chordoma tumorigenesis.
- Carbonic anhydrase II (CA2) is a novel therapeutic target for chordoma.
- Dorzolamide HCl shows promise as a therapeutic option for chordoma.
