Meningiomas are the most frequent intracranial brain tumours. Current treatment
options of surgery and radiotherapy are sometimes insufficient and effective
systemic therapies remain unestablished. The development of accurate in vitro
systems to model the complexity of meningioma pathology is essential for
predicting drug response and developing novel therapeutics. Therefore, in this
study, I established an easy-to-use in vitro patient-derived meningioma spheroid
model that maintained the morphological and molecular features of the parental
tumours, including tissue histology, the tumour microenvironment, and the
mutational profile. Comprehensive characterisation of the global transcriptomes
of the novel patient-derived spheroids with traditional meningioma monolayer
cultures and parental tissues revealed an enhanced Notch1-mediated
mesenchymal gene expression signature in the spheroids compared to traditional
2D monolayer cultures. These features were confirmed by the presence of other
mesenchymal traits such as invasion capacity, demonstrating this spheroid
model as the first meningioma 3D culture method capable of studying functional
invasion, and indicating its relevance for studying the molecular mechanisms
associated with invasion and the related oncogenic process of epithelial-tomesenchymal
transition (EMT). The suitability of this model for use as a tool for
research questions, including pre-clinical drug testing, was demonstrated by
studying the effect of Notch1 shRNA targeting, and by treatment using several
inhibitors. Concomitantly, this proof-of-concept study allowed for the
development of a novel effective combination therapy of MER tyrosine kinase
(MERTK) and histone deacetylase (HDAC) inhibition, which in addition to having
a synergistic inhibitory effect on spheroid viability, also decreased spheroid
proliferation, expression of EMT-associated proteins and spheroid invasion
capacity. Hence, I propose this meningioma spheroid model as novel preclinical
drug screening tool to assess the efficacy of drug compounds targeting EMT and
brain invasion of meningiomas and the combination of HDAC and MERTK
inhibitors as a promising therapeutic strategy.
Date of Award | 2024 |
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Original language | English |
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Awarding Institution | |
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Supervisor | Oliver Hanemann (Other Supervisor) |
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- Meningioma
- 3D culture
- spheroids
The development and validation of a novel patient-derived 3D meningioma cell culture model
van de Weijer, L. L. (Author). 2024
Student thesis: PhD