| Summary: | 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.
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