MBRS-03. SINGLE NUCLEUS TRANSCRIPTOME PROFILES FROM HUMAN DEVELOPING CEREBELLUM REVEAL POTENTIAL CELLULAR ORIGINS OF MEDULLOBLASTOMA BRAIN TUMORS

Medulloblastoma (MB) is a highly malignant pediatric brain tumor originating from the cerebellum and brainstem. Identification of molecular subgroups forming this heterogeneous tumor entity was initially achieved from transcriptome characterization and further strengthened using DNA methylation profiling. While subgroup classification improved clinical diagnosis and treatment options, the lack of knowledge of the cell-of-origin for some of the subgroups hinders further treatment improvements. In addition identification of the precise cells of origin for each subgroup could help to understand tumor cell biology. Single cell sequencing is the optimal way to solve this task; recently, there were attempts to uncover putative MB cell-of-origin by using such information obtained from mouse embryonic cerebellum. However, such a comparative strategy can miss important results due to the differences between mouse and human. To solve this issue, we performed global single nucleus sequencing on human cerebellum pre- and postnatal materials across several developmental time points and generated transcriptome profiles from ~200k single cells. We identified known cell types forming the human cerebellum and performed detailed comparison of normal cells to RNA-seq bulk data from MB brain tumors across all subgroups. By selecting an optimal analysis strategy, we verified granule neuron precursors as cells of origin for the SHH MB subgroup. Additionally, we also found other cell types in conjunction with the remaining MB subgroups, suggesting new potential targets for investigation. Notably, this strategy can be further applied to the examination of other brain tumors and has perspectives in medical application.