Fairchild, Amy R.; (2022) Developing models of high-grade paediatric brain tumours and investigating divergent differentiation in medulloblastoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction. Brain tumours are the commonest cause of death in children. They are often difficult to diagnose, demonstrate clinically aggressive behaviour and a poor prognosis. Challenges include a lack of representative disease-specific cell culture models, and a gap in our understanding regarding the fundamental biology of differentiation. Having established a cell culture of a rare example – medulloblastoma with divergent differentiation (MBDD), I undertook a literature review and established a cohort of these tumours to explore the biology of heterologous differentiation. / Methods. I set up a mechanism at Great Ormond Street Hospital to routinely collect resected brain tumour tissue for research. Samples were dissociated into single cell suspensions and grown in vitro. Cultures were characterised by their immunohistochemical and DNA methylation profiles and directly compared to their original patient tumour sample at diagnosis. I established the largest described cohort (n = 18) of MBDDs and performed immunohistochemistry for myogenic, melanotic and epithelial markers. I classified the cohort by their DNA methylation profiles and analysed their transcriptomes by bulk RNA-sequencing. / Results. I generated representative cell culture models including highgrade gliomas, medulloblastomas and atypical teratoid/rhabdoid tumours (ATRTs). Furthermore, I demonstrated that divergent differentiation occurs in a small subset of medulloblastomas – the majority of which classify as molecular group 3, subtype II. I showed that MBDDs have different transcriptomic profiles to non-divergent medulloblastomas. MBDDs are associated with a relatively reproducible activation of gene networks that control differentiation (i.e., myogenesis), and other general signalling pathways (i.e., hippo signalling). / Conclusion. This thesis contributes a range of primary cell cultures to be used for further research. The ability to model these diseases will increase our understanding of their underlying pathobiology, aiding the identification of novel therapeutic targets. Secondly, this thesis identifies an underlying mechanism of heterologous differentiation in medulloblastoma, hypothesizing that this phenomenon is driven by YAP overactivation in progenitor cells.

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