PDTM-21. MATCHING OF SINGLE CELL TRANSCRIPTOMICS FROM CEREBELLAR DEVELOPMENT IDENTIFIES PUTATIVE SUBGROUP SPECIFIC CELLS OF ORIGIN FOR MEDULLOBLASTOMA
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Abstract We isolated cells from various points in murine embryonic and early post-natal cerebellar development (E10 to P14) and undertook single cell RNA sequencing to identify >30 transcriptionally distinct cell populations. Reconstruction of developmental lineages in the developing cerebellum through pseudotemporal analysis demonstrate that a progenitor cell population from the upper rhombic lip gives rise to both the external granule cell layer (EGL) and the previously under-studied unipolar brush cells (UBC). Unipolar brush cells are a glutamatergic interneuron most prevalent in the inferior and lateral cerebellum. Transcriptional matching of bulk human tumor RNA-seq data from human patients demonstrates subgroup specific transcriptional resemblances. As expected, Shh MBs resemble the developing EGL. Fascinatingly, only Shh tumors that transcriptionally mirror earlier, but not later EGL developmental time points were found to be metastatic in human patients. Group 3 tumors have a resemblance to early Nestin +ve stem cells across the entire subgroup, with additional similarities to the EGL, UBC, and GABAergic interneurons. Unexpectedly, Group 4 tumors were vastly most similar to UBCs, and on further analysis to a single known subset of UBCs (Calb2+ve UBCs). Single cell RNA-seq from human medulloblastomas (Shh, Group 3, and Group 4 MB) largely confirms the transcriptional similarities to murine cerebellar developmental lineages observed in the bulk RNA-seq data, but also demonstrates that most medulloblastomas have multiple distinct tumor cell clusters. Distinct single cell expression clusters from an individual MB demonstrate that there is a developmental lineage or hierarchy of cells with most tumors, that this hierarchy is likely hardwired from normal development, and that bulk tumor data in fact reflects a heterogeneous cell population. These data pinpoint possible cells of origin for medulloblastoma subgroups, illustrate a further layer of MB heterogeneity, and allow a comparison of normal and MB transcriptomes to further understand MB biology.
