ORCID
- Claire Adams: 0000-0003-3871-9267
- Matt Banton: 0000-0002-9199-7170
- Vikram Sharma: 0000-0002-3833-7763
- Emanuela Ercolano: 0000-0001-7471-9374
- Waldemar Woznica: 0009-0008-3989-5039
- David Parkinson: 0000-0002-5704-4923
- Leandro Jose De Assis: 0000-0001-9782-437X
- Oliver Hanemann: 0000-0002-1951-1025
Abstract
Background: Meningiomas, the most common primary brain tumours, are classified by the World Health Organization (WHO) into grades 1, 2, and 3. Some grade 1 tumours exhibit increased clinical aggressiveness, with the biallelic mutation of NF2 being the most frequently reported. Methods: In our study, we analysed the most common driver mutations (NF2, AKT1, KLF4, and TRAF7) in meningioma by genomics describing co-occurrences and new mutations. Furthermore, tumour tissue bearing the driver mutations was analysed by proteomics. The relevance of the specific target found in the most common driver mutation in meningiomas (NF2) was validated in vitro using both lower and higher-grade meningioma and further, the higher-grade meningioma was analysed in vivo using an NOD scid gamma (NSG) mouse model. Findings: Our genomic data revealed co-occurrences of non-NF2 mutations in lower-grade meningiomas, suggesting synergistic effects supporting tumour growth. NF2 −/− meningiomas showed distinct proteomic clustering, with different mutations found in these clusters. Additionally, proteomics identified Annexin-3 (ANXA3) upregulated in NF2 −/− meningioma. Its role in proliferation was confirmed in grade 1 and subsequently grade 3 tumours in vitro and with abolished growth when knocked down in a meningioma mouse model. Interpretation: These findings highlight new targets in different meningioma backgrounds, presenting ANXA3 as a potential therapeutic target for meningioma treatment. Funding: This work was funded by the Brain Tumour Centre of Excellence.
DOI Link
Publication Date
2025-06-25
Publication Title
eBioMedicine
Volume
117
Acceptance Date
2025-06-04
Deposit Date
2025-07-01
Funding
We would like to acknowledge the Neurosurgical Nurse Practitioners at North Bristol NHS Trust and the Assistant Practitioner for Research at University Hospitals Plymouth NHS Trust for their role in obtaining patient consent. Special thanks to the pathology teams at both trusts for providing excess tumour tissue following diagnostic testing, and to the neurosurgeons for facilitating the process of sending fresh tissue samples to the pathology laboratories. We are also grateful to Dr Sarah Kingdon for assisting with patient consent and for her efforts in correlating clinical data. Tissue samples were sourced from University Hospitals Plymouth NHS Trust as part of the BRAIN UK initiative, which is supported by Brain Tumour Research and was established with the backing of the British Neuropathological Society and the Medical Research Council . We also acknowledge Felix Sahm from Heidelberg for his support with bioinformatics and genetic analysis.
Keywords
AKT1, ANXA3, KLF4, Meningioma, NF2, TRAF7
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Shah, M., Akther, Y., Adams, C., Banton, M., Sharma, V., Ercolano, E., Hilton, D., Kurian, K., Laraba, L., Woznica, W., Parkinson, D., De Assis, L., & Hanemann, O. (2025) 'Integrated proteomic and targeted Next Generation Sequencing reveal relevant heterogeneity in lower-grade meningioma and ANXA3 as a new target in NF2 mutated meningiomas', eBioMedicine, 117. Available at: 10.1016/j.ebiom.2025.105814
