Background
Astrocytoma is a diffuse and heterogeneous glioma that infiltrates the brain. Despite post-operative therapy including radiation and chemotherapy, 52% of patients’ tumours recur within five-years of surgery. These tumours are characterised by mutations in the IDH1 or IDH2 gene that confer metabolic alterations, most notably the production of the onco-metabolite 2-hydroxyglutarate. To reveal the metabolic alterations and their upstream regulation across the heterogeneous tumour microenvironment, we applied spatial metabolomics and spatial transcriptomics to sequential sections from resected tumour samples of patients with low grade astrocytoma.
Methods
Spatial assessment of heterogeneity was performed on serial sections using spatial metabolomics (atmospheric pressure MALDI-TOF) and spatial transcriptomics (10X Genomics Xenium). This necessitated extensive optimisation of image registration across modalities and sequential sections to create three dimensional models to deeply interrogate heterogeneity within tumours.
Results
Combining spatial transcriptomics and spatial metabolomics across 8 matched sequential slices of the same patient tumour, enabled the identification of metabolic niches associated with distinct cell type composition and transcriptional regulation. Strikingly, normal domains that were present at the leading edge of tumours could be identified both metabolically and transcriptomically.
Conclusions
Understanding the heterogeneity of astrocytomas on a spatial level reveals unique domains and organisation of tumour and immune cell types. Matching these transcriptomic and cell state information with metabolism leads to pathway insights that will be essential to the identification of druggable targets. Our pipeline combining spatial transcriptomics and metabolomics with tissue histology reveals these biologically important domains.