Medulloblastoma Spatial Transcriptomics Reveals Tumor Microenvironment Heterogeneity With High-Density Progenitor Cell Regions Correlating With High-Risk Disease.

purposeNo 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.

methodsWe 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.

resultsOur 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.

conclusionOur 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.