Medulloblastoma is one of the most common pediatric malignant brain tumors, currently comprising four distinct molecular subgroups: wingless [WNT], sonic hedgehog [SHH], and groups 3-4. Efforts to identify the mechanisms of medulloblastoma development have focused on mapping the extent of the tumor cell heterogeneity within each subgroup. Nevertheless, little is known about the role of the tumor microenvironment (TME) in medulloblastoma progression, particularly in subgroups 3-4, which have the worst prognosis due to metastatic disease. In this study, we performed single-cell transcriptomics on 14 human medulloblastoma samples spanning all molecular subgroups, to uncover novel TME-tumor interactions modulating medulloblastoma progression and metastasis. Unsupervised clustering of all medulloblastoma samples revealed 18 subclusters, including tumor granule neuron progenitors (GNPs) in different stages of differentiation, stromal cells (including oligodendrocyte precursors, mature oligodendrocytes, astrocytes, fibroblasts, endothelial cells and pericytes), myeloid cells (including microglia, monocytes and macrophages) as well as lymphoid cells. To investigate subgroup-specific signatures as well as TME-tumor pathways, we analyzed each subgroup separately. Analysis of supporting stroma cells in groups 3-4 demonstrated the presence of 8 different stroma populations, including a population of tumor-associated endothelial cells. Tumor-associated endothelial and fibroblast populations of groups 3-4 showed the highest expression of genes for vascular remodeling and extracellular matrix degradation, suggesting an active reprogramming of the stroma by tumor GNP cells to support medulloblastoma progression. Epithelial-to-mesenchymal transition-like processes that regulate stem cell, invasion and metastatic properties were upregulated in the tumor GNP populations of groups 3-4 compared to SHH and WNT subgroups. Finally, we highlight the presence of the CXCL1-CXCL5/CXCR2 metastasis-associated axis in groups 3-4 medulloblastomas as a potential therapeutic target. Our findings provide biological insights into TME processes for the different subgroups of medulloblastoma and possible new potential therapeutic avenues. Citation Format: Ioanna Tsea, Yana Ruchiy, Manouk Verhoeven, Indranil Sinha, Klas Blomgren, Lena Maria Carlson, John Inge Johnsen, Cecilia Dyberg, Ninib Baryawno. Transcriptomic landscape of medulloblastoma reveals pathways of tumor-stroma remodelling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1677.
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