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Pandele, Alina Gabriela (2024) Integrating transcriptomics and metabolomics to analyse and target tumour heterogeneity in paediatric ependymoma. PhD thesis, University of Nottingham.

PDF (Final thesis submission with corrections) (Thesis - as examined) - Repository staff only until 17 July 2026. Subsequently available to Anyone - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader Available under Licence Creative Commons Attribution. Download (6MB)

Abstract

Ependymoma (EPN) is the second most malignant paediatric brain tumour which has a five-year survival rate of 25% following relapse. Given the close association between gene expression, active biochemical signalling and metabolism, there is an unmet scientific need to determine whether dysregulated EPN gene expression correlates with aberrant metabolic pathways, which may present therapeutic vulnerabilities. In this context, we present a multi-omics integration at transcriptomic and metabolomics levels.

First, surgically resected EPN tissue from two epigenetic subgroups, posterior fossa-A (PF-A) and supratentorial RELA, were first homogenised and metabolites, lipids and RNA simultaneously extracted from the same cellular population ensuring transcriptomic/metabolomic integration is reflective of the same cellular state and disease snapshot. Using liquid chromatography-mass spectrometry (LC-MS) and RNAseq we identified 1580 differential genes and 115 differentially abundant metabolites between the two subgroups which were integrated to uncover dysregulated metabolic pathways.

Secondly, to reveal whether spatially-distinct tumour microenvironments represent heterogeneous metabolic niches in EPN, transcriptomic and metabolomics data was next analysed comparing intra-tumour regions from eight patients diagnosed with PF-A EPN. Multi-omics integration revealed 124 therapeutically relevant metabolic pathways critical for EPN survival, thus circumventing patient-specific genetic profiles.

Finally, we identified a subset of the nine most prevalent metabolically relevant genes across patients, which were selected for in vitro functional assays using 11 repurposed cytotoxic agents against PF-A EPN cell lines derived from intra-tumour regions of the same patients. Based on current literature, this is the first instance where multi-omic data integration and intra-tumour heterogeneity has been investigated for paediatric EPN, revealing novel potential targets in the context of gene-metabolite correlations.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Rahman, Ruman Grundy, Richard
Keywords:	Ependymoma; Brain tumour; Biochemical signalling; Gene expression; Intra-tumour heterogeneity
Subjects:	W Medicine and related subjects (NLM Classification) > WL Nervous system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	77459
Depositing User:	Pandele, Alina
Date Deposited:	24 Jul 2024 13:37
Last Modified:	24 Jul 2024 13:37
URI:	https://eprints.nottingham.ac.uk/id/eprint/77459

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