Abstract
Medulloblastoma is the most common malignant brain tumour of childhood. While our understanding of this disease has progressed substantially in recent years, the role of tumour microenvironment remains unclear. Given the increasing role of microenvironment-targeted therapeutics in other cancers, this study was aimed at further exploring its role in medulloblastoma. Multiple computational techniques were used to analyze open-source bulk and single cell RNA seq data from primary samples derived from all subgroups of medulloblastoma. Gene expression is used to infer stromal subpopulations, and network-based approaches are used to identify potential therapeutic targets. Bulk data was obtained from 763 medulloblastoma samples and single cell data from an additional 7241 cells from 23 tumours. Independent bulk (285 tumours) and single cell (32,868 cells from 29 tumours) validation cohorts were used to verify results. The SHH subgroup was found to be enriched in stromal activity, including the epithelial-to-mesenchymal transition, while group 3 is comparatively stroma-suppressed. Several receptor and ligand candidates underlying this difference are identified which we find to correlate with metastatic potential of SHH medulloblastoma. Additionally, a biologically active gradient is detected within SHH medulloblastoma, from “stroma-active” to “stroma-suppressed” cells which may have relevance to targeted therapy. This study serves to further elucidate the role of the stromal microenvironment in SHH-subgroup medulloblastoma and identify novel treatment possibilities for this challenging disease.
Highlights
Medulloblastoma is the most common malignant brain tumour of childhood
We further explored the above characteristics of stromal microenvironment in the more refined molecular subclasses of medulloblastoma defined through the integration of multimodal genomic data (Cavalli et al.2)
We investigated the cell-level gene expression programs associated with the distinct tumor microenvironment (TME) phenotypes observed in SHH medulloblastoma (Fig. 4A)
Summary
Medulloblastoma is the most common malignant brain tumour of childhood. While our understanding of this disease has progressed substantially in recent years, the role of tumour microenvironment remains unclear. This study serves to further elucidate the role of the stromal microenvironment in SHH-subgroup medulloblastoma and identify novel treatment possibilities for this challenging disease. Placental growth factor has been proposed as a key mediator of tumor-stroma interactions in medulloblastoma with possible therapeutic appeal, though its subgroup-specific role is unclear[11]. In this exploratory study, we apply established computational methods to well-annotated bulk and single cell medulloblastoma transcriptomic data in order to better define its stromal microenvironment and identify targetable pathways with therapeutic potential
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