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Published on: August 25, 2023
Clinical-proteomic classification and precision treatment strategy of chordoma
Huabin Yin1, Jinbo Hu2, Jianxuan Gao3
1Department of Orthopedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Abstract:
Chordoma is a rare and heterogeneous mesenchymal malignancy, with distinct clinical and biological behaviors. Till now, its comprehensive clinical-molecular characteristics and accurate molecular classification remain obscure. In this research, we enroll 102 patients with chordoma and describe their clinical, imageological, and histopathological features. Through tandem mass tag-based proteomic analysis and nonnegative matrix factorization clustering, we classify chordoma into three molecular subtypes: bone microenvironment-dominant, mesenchymal-derived, and mesenchymal-to-epithelial transition-mediated pattern. The three subtypes exhibit discrete clinical prognosis and distinct biological attributes of osteoclastogenesis and immunogenicity, oxidative phosphorylation, and receptor tyrosine kinase activation, suggesting targeted therapeutic strategies of denosumab, S-Gboxin, and anlotinib, respectively. Notably, these approaches demonstrate positive treatment outcomes for each subtype in vitro and in vivo. Altogether, this work sheds light on the clinical-proteomic characteristics of chordoma and provides a candidate precision treatment strategy for chordoma according to molecular classification, underscoring their potential for clinical application.
Insights
This study classifies chordoma, a rare bone cancer, into three molecular subtypes using proteomic analysis. These subtypes inform precision treatment strategies, improving patient outcomes.
Area of Science:
- Oncology
- Proteomics
- Molecular Biology
Background:
- Chordoma is a rare, heterogeneous mesenchymal malignancy with poorly understood clinical-molecular characteristics.
- Accurate molecular classification of chordoma is essential for developing effective therapeutic strategies.
Purpose of the Study:
- To comprehensively characterize the clinical-molecular features of chordoma.
- To classify chordoma into distinct molecular subtypes.
- To identify subtype-specific targeted therapies.
Main Methods:
- Proteomic analysis using tandem mass tag (TMT) labeling.
- Nonnegative matrix factorization (NMF) clustering for molecular subtyping.
- In vitro and in vivo validation of therapeutic strategies.
Main Results:
- Chordoma classified into three molecular subtypes: bone microenvironment-dominant, mesenchymal-derived, and mesenchymal-to-epithelial transition-mediated.
- Each subtype exhibits distinct clinical prognosis and biological attributes (osteoclastogenesis, immunogenicity, oxidative phosphorylation, RTK activation).
- Targeted therapies (denosumab, S-Gboxin, anlotinib) showed positive outcomes for specific subtypes.
Conclusions:
- This research elucidates the clinical-proteomic landscape of chordoma.
- A molecular classification system for chordoma is proposed.
- Precision treatment strategies tailored to molecular subtypes demonstrate therapeutic potential for chordoma.
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