105 Single-Cell Omics Approach Identifies Subtype-Specific Evolutionary Pathways and Therapeutic Targets in Spinal Ependymomas

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INTRODUCTION: Spinal ependymomas can range from relatively indolent (WHO Grade2) to aggressive Grade3 and MYCN-amplified subgroups. the molecular mechanisms, and evolutionary relationships between these subgroups are currently unknown, impeding the development of targeted therapies. METHODS: We performed paired single-nucleus RNA sequencing (snRNA-seq) and chromatin accessibility (snATAC-seq) on Grade2 (n=3; 2 patients), Grade3 (n=2) and MYCN-amplified (n=4) spinal ependymomas. Comparative analyses were conducted using publicly available tumor snRNA-seq (grade2: n=8; grade3: n=2), and normal ependymal samples (n=15). Tumor and normal ependymal populations (1.75x10^5 cells) were integrated to assess transcriptional and transcription factor (TF) regulatory programs, and evolutionary relationships across tumor subgroups. RESULTS: Differential gene expression analysis revealed upregulation of MYC targets in Grade2 tumors compared to normal ependymal cells. KRAS/WNT upregulation was seen in Grade3, and MYCN and Unfolded Protein Response genes were upregulated in MYCN-amplified tumors. There were no consensus dysregulated molecular pathways between subgroups. There was no difference in global chromatin accessibility, however TF inference demonstrated epithelial-to-mesenchymal (EMT) TFs (SNAI1, SNAI3) drive Grade2, and TGF-Beta TFs (SMAD3, SMAD2) drive Grade3 tumors. MYCN-amplified tumors were driven by the Hippo Pathway (TEAD 1-4, JUN/FOS, CTCF), and oncogenic TFs (NFAT5, ETV5). Partition-based graph abstraction of transcriptional states suggested that spinal ependymoma subgroups originate independently from normal ependymal tissue, with no evidence supporting a shared precursor or evolutionary sequencing between groups. CONCLUSIONS: Our findings provide a comprehensive view of the molecular heterogeneity of spinal ependymomas. Spinal ependymomas subgroups likely evolve independently, with distinct molecular signatures. Our results suggest that subtype-specific therapeutic targeting may be feasible, such as targeting EMT for Grade2, SHH for Grade3, and Hippo for MYCN-amplified ependymomas. We lay the groundwork for precision medicine approaches for treating spinal ependymomas.

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