Medulloblastoma Spatial Transcriptomics Reveals Tumor Microenvironment Heterogeneity With High-Density Progenitor Cell Regions Correlating With High-Risk Disease.
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PURPOSE: No curative options are available for medulloblastoma (MB) in the relapse setting. The tumor microenvironment (TME) influences progression and therapy response, presenting a promising target for therapeutic advances. Prior single-cell analyses have characterized the cellular components of the TME but lack spatial context. We hypothesize that spatial architecture, beyond cell composition, influences tumor progression and treatment outcomes. METHODS: We performed spatial transcriptomic sequencing on 18 pediatric MB samples obtained at diagnosis, including two matched diagnosis-relapse pairs. Samples at diagnosis were stratified into high- and standard-risk groups. Spatial data were analyzed for spatial proximity to other cell types, cell-cell communication networks, and expression of cell cycle dormancy signatures. Findings were validated using immunohistochemistry in the same cohort. RESULTS: Our analyses revealed intertumoral and intratumoral heterogeneity within the TME, comprising tumor-associated astrocytes (TAAs), macrophages (TAMs), stromal components, and distinct subpopulations of MB cells at different stages of neuronal differentiation and cell cycle progression. We identified dense regions of quiescent progenitor-like MB cells enriched in patients with high-risk (HR) features and an increase in TAAs, TAMs, and dysregulated vascular endothelium following relapse. CONCLUSION: Our study presents novel insights into the spatial architecture and cellular landscape of the MB-TME, highlighting differential spatial patterns correlating with HR features. Future studies should evaluate their role in relapse and therapy resistance and may lead to uncovering novel therapeutic targets.