Single-cell RNA-seq Reveals a Developmental Hierarchy and Oncogenic Networks for Initiation of Medulloblastoma [ATAC-Seq]

By utilizing single-cell analysis at different stages of tumorigenesis, we demonstrated a developmental hierarchy of dynamic progenitor pools in murine sonic hedgehog-(SHH) MBs. We identified Olig2+ progenitors as transit-amplifying cells during initial tumorigenic phases. These cells are quiescent stem-like progenitors in full-blown tumors but enriched in therapy-resistant as well as recurrent medulloblastomas. Olig2 ablation or depletion of mitotic Olig2+ progenitors abrogated tumorigenesis. Transcriptome profiling and chromatin occupancy assays revealed that Olig2 activates oncogenic networks including HIPPO- Yap/Taz signaling and Aurora-A/MycN pathways. Co-targeting these oncogenic pathways induced sustained tumor growth arrest. Together, our single-cell analyses uncover unexpected glia-lineage-related Olig2+ progenitor pools critical for medulloblastoma initiation and suggest targeting Olig2-regulated oncogenic pathways as an avenue for therapy. 2 ATAC-Seq samples from mice medulloblastoma tumor cells (ATAC_Olig2_GFP(-), ATAC_Olig2_GFP(+))