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  3. Multiplatform molecular analyses reveal two molecular subgroups of NF2-related schwannomatosis vestibular schwannomas with distinct tumour microenvironment and therapeutic vulnerabilities

Multiplatform molecular analyses reveal two molecular subgroups of NF2-related schwannomatosis vestibular schwannomas with distinct tumour microenvironment and therapeutic vulnerabilities

  • Acta Neuropathol. 2025 May 9;149(1):47. doi: 10.1007/s00401-025-02883-6.
Fu Zhao # 1,  Xu-Fei Teng # 2 3,  Jing Zhang # 4,  Shi-Wei Li # 5,  Lei-Ming Wang 6,  Han-Guang Zhao 7,  Shun Zhang 5 8,  Chi Zhao 9,  Peng Li 5,  Xiao-Bin Zhao 10,  Shu-Hui Song 11,  Pi-Nan Liu 12 13
Affiliations

Affiliations

  • 1 Department of Pediatric Neurosurgery, Beijing Key Laboratory of Drug Innovation for Neuro-Oncology, Beijing Neurosurgical Institute, Capital Medical University, 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, People's Republic of China. zhaofu@ccmu.edu.cn.
  • 2 National Genomics Data Center, China National Center for Bioinformation & Beijing Institute of Genomics, Chinese Academy of Sciences, No. 1 Beichen West Road, Chaoyang District, Beijing, 100101, People's Republic of China.
  • 3 Department of Neurology, Yale School of Medicine, New Haven, CT, 06511, USA.
  • 4 Department of Neural Reconstruction, Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University, 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, People's Republic of China.
  • 5 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, People's Republic of China.
  • 6 Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China.
  • 7 Department of Pediatric Neurosurgery, Beijing Key Laboratory of Drug Innovation for Neuro-Oncology, Beijing Neurosurgical Institute, Capital Medical University, 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, People's Republic of China.
  • 8 Department of Neurosurgery, Beijing Hospital, Peking Union Medical College, Beijing, People's Republic of China.
  • 9 Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, People's Republic of China.
  • 10 Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.
  • 11 National Genomics Data Center, China National Center for Bioinformation & Beijing Institute of Genomics, Chinese Academy of Sciences, No. 1 Beichen West Road, Chaoyang District, Beijing, 100101, People's Republic of China. songshh@big.ac.cn.
  • 12 Department of Neural Reconstruction, Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University, 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, People's Republic of China. pinanliu@ccmu.edu.cn.
  • 13 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, People's Republic of China. pinanliu@ccmu.edu.cn.
  • # Contributed equally.
PMID: 40343504 DOI: 10.1007/s00401-025-02883-6
Abstract

NF2-related schwannomatosis (NF2-SWN) is a genetic predisposition syndrome characterized by the development of bilateral vestibular schwannomas (VSs). Despite their benign nature and consistent histopathological characteristics, these tumours display significant clinical and therapeutic heterogeneity. To elucidate the molecular heterogeneity within NF2-SWN schwannomas, we performed comprehensive molecular analyses on a cohort of 70 patients with NF2-SWN, including bulk RNA Sequencing, whole genome or exome Sequencing, single nuclear RNA (snRNA) Sequencing and immunohistochemistry. Our analysis identified two distinct molecular subgroups: immune-enriched schwannomas (IESs) and immune-depleted schwannomas (IDSs). IESs were commonly diagnosed in adulthood, followed a favorable prognosis, and were characterized by abundant macrophage infiltration within the tumour microenvironment. In contrast, IDSs were predominantly composed of Schwann cells, harbored germline NF2 mutations, occurred primarily during childhood and had poorer outcomes. Immunohistochemical staining for ionized calcium-binding adaptor molecule 1 (Iba1) and CD68, CD163 antibodies effectively differentiated these two subgroups of NF2-SWN schwannomas. Furthermore, we demonstrated that blockade of the colony stimulating factor 1 receptor (CSF1R) resulted in macrophage depletion and significantly suppressed tumour growth in both in vitro and in vivo models of IESs. Collectively, our study reveals two discrete molecular subgroups within NF2-SWN schwannomas, highlighting the importance of considering these subgroups in future therapeutic research and clinical trial design.

Keywords

NF2-related schwannomatosis; Macrophage; Molecular subgroup; Tumour microenvironment; Vestibular schwannoma.

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