Molecular landscape, subtypes, and therapeutic vulnerabilities of central nervous system solitary fibrous tumors

Chenhui Zhao, Xueyan Hu, Xiudong Guan, Xiaojun Fu, Tingting Wang, Mengyuan Li, Xinze Liu, Jiarui Zhao, Di Wu, Fan Zhang, Jiaying Fu, Jiang Li, Tieqiang Zhang, Xiaochun Jiang (), Changxiang Yan (), Wang Jia (), Ence Yang () and Jian Chen ()
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Chenhui Zhao: Chinese Academy of Medical Sciences & Peking Union Medical College
Xueyan Hu: Peking University Health Science Center
Xiudong Guan: Capital Medical University
Xiaojun Fu: Haidian District
Tingting Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Mengyuan Li: Chinese Academy of Medical Sciences & Peking Union Medical College
Xinze Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
Jiarui Zhao: Chinese Academy of Medical Sciences & Peking Union Medical College
Di Wu: Chinese Academy of Medical Sciences & Peking Union Medical College
Fan Zhang: The First Affiliated Hospital of Wannan Medical College
Jiaying Fu: Chinese Academy of Medical Sciences & Peking Union Medical College
Jiang Li: Capital Medical University
Tieqiang Zhang: Capital Medical University
Xiaochun Jiang: The First Affiliated Hospital of Wannan Medical College
Changxiang Yan: Haidian District
Wang Jia: Capital Medical University
Ence Yang: Peking University Health Science Center
Jian Chen: Chinese Academy of Medical Sciences & Peking Union Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Solitary fibrous tumors (SFTs) of the central nervous system (CNS) are rare, aggressive mesenchymal neoplasms with high recurrence and metastasis rates. Here, we perform a comprehensive multi-omics analysis of 189 cases of CNS SFTs integrating 94 whole genome sequencing, 88 transcriptomics, 7 single-nucleus RNA sequencing and 3 spatial transcriptome sequencing. We find that receptor tyrosine kinase mutations are significantly more prevalent besides the widespread NAB2-STAT6 fusion and correlate with tumor grade. Transcriptomic analysis reveals four molecular subtypes—classical, neural-like, inflamed and migratory—each associated with distinct clinical and biological characteristics. Single-nucleus RNA sequencing identifies five tumor cell states, with the SFT_classical state serving as a precursor to other states influenced by hypoxia and inflammation. Notably, we identify FER kinase as a key therapeutic target, with FER inhibition significantly reducing tumor cell proliferation, migration and invasion. These findings provide important insights into CNS SFT biology and suggest potential therapeutic strategies for this challenging tumor type.

Date: 2025
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DOI: 10.1038/s41467-025-63039-4

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