Targeting Aldehyde Dehydrogenases in NF2-null Meningioma and Schwannoma

Abstract

Meningioma and schwannoma are tumours of the brain and nervous system that are frequently driven by loss or mutation of the gene NF2, which encodes the tumour suppressor protein Merlin. Dysregulated Hippo pathway signalling, caused by NF2 loss, drives overexpression of aldehyde dehydrogenase 1A1 (ALDH1A1) in NF2-null schwannoma. High expression of ALDH1A1, and the related isoform ALDH1A3 have been identified as markers of cancer stem cell activity and have been correlated with poor prognosis and chemoresistance in several cancers. This project aims to clarify the role of
aldehyde dehydrogenase (ALDH) enzymes in meningioma tumours and evaluate their potential as future therapeutic targets in meningioma and schwannoma.

Use of the Aldefluor assay revealed distinct ALDH high activity (ALDH^high) populations in low- and high-grade NF2-null meningioma cell lines. Isolation of these cells using fluorescence-activated cell sorting reveals superior colony forming ability in the ALDH^high cells compared with ALDH^low. Western blotting and immunostaining were used to confirm that ALDH1A3 specifically is strongly expressed in meningioma cells and tissue. ALDH1A3-targeted shRNA knockdown deplete colony formation, proliferation, and ALDH activity in these cells.

The ALDH inhibitors nifuroxazide, DIMATE, and ABD 0171 reduce the proliferation and/or survival of meningioma cells. ABD 0171 also reduces tumour growth fold change and cell proliferation in the murine meningioma xenograft model. Nifuroxazide, which inhibits ALDH1A1 and ALDH1A3, drives a reduction in cell proliferation in dorsal root and vestibular ganglia schwannomas in the NF2fl/fl Periostin-CRE mouse schwannoma model, and in meningioma murine orthotopic xenograft tumours.

In summary, this project has revealed a significant role for ALDH enzymes, particularly ALDH1A3, in driving tumour growth in meningioma cells. Encouragingly, ALDH inhibitors have shown strong anti-tumour efficacy in vitro and in vivo. Taken together, the results obtained in this PhD project suggest that ALDH enzymes may represent a key therapeutic vulnerability in NF2-null meningioma and schwannoma tumours, worthy of further exploration.

Date of Award	2025
Original language	English
Awarding Institution	University of Plymouth
Sponsors	Brain Tumour Research
Supervisor	David Parkinson (Director of Studies (First Supervisor)), Sylwia Ammoun (Other Supervisor) & Oliver Hanemann (Other Supervisor)