GENE-21. A COMMON FETAL DEVELOPMENTAL ORIGIN FOR PFA EPENDYMOMA, PFB EPENDYMOMA, AND CEREBELLAR PILOCYTIC ASTROCYTOMAS?
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Abstract Single cell RNA-sequencing (scRNAseq) of murine cerebellum at nine fetal and immediate post-natal (E10-P14) times points on >60,000 individual cells to identified >30 transcriptionally distinct cell clusters. Based on marker gene expression, many clusters resemble known cerebellar stem, progenitor, and differentiated cell types, while other clusters are more novel. Pseudo-time trajectory assisted in the reconstruction of known and novel developmental lineages, including the lineage of the cerebellar radial glia. A population of stem cells in the ventricular zone (VZ) gives rise to the progenitors of the GABAergic cerebellar interneurons, as well as the gliogenic progenitor cells, which subsequently become Bergmann glia and astrocytes. A novel, but clearly distinct and robust cluster of cells with transcriptional similarity to both the roof plate and the rhombic lip was identified. Comparison of bulk RNA-seq from human PFA, PFB, and cerebellar pilocytic astrocytomas (C-PA) reveals that all three-tumor types best transcriptionally match the gliogenic progenitor cells, with some similarity to VZ stem cells and the ‘roof plate like’ stem cells. Furthermore, all three tumor types are transcriptionally much more similar to the gliogenic progenitors at E16 than at E14 or E18. Subclustering of gliogenic progenitors reveals significant intra-cluster heterogeneity, with the ependymomas transcriptionally matching one subcluster, and the C-PA clearly matching a very different subcluster. scRNAseq of human PFA and PFB ependymomas reveals multiple tumor cell clusters within a given human ependymoma, with some clusters matching most closely to the gliogenic progenitors, and others matching best to the ‘roof plate like’ stem cells. Similarity to the ‘roof plate stem cells’ (E10-E14), and gliogenic progenitors (E14-E18) suggests an embryonic origin for PFA, PFB, and C-PA, suggests specific novel cells of origin, and offers a novel opportunity to understand posterior fossa tumor transcriptomic targets for novel therapy.
