Mapping the Cerebellar Origins of Medulloblastoma Subgroups

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PROJECT SUMMARY Childhood cancers are the consequence of failed normal development. Medulloblastoma (MB), a malignant embryonal tumor of the cerebellum, exemplifies a highly aggressive pediatric cancer driven by aberrant activation of neurodevelopmental pathways and disruption of neuronal differentiation programs. Genomics has effectively divided MB into biologically and clinically distinct consensus molecular subgroups, including WNT, SHH, Group 3, and Group 4. Mouse tumor modeling studies have substantiated the cellular origins of WNT- and SHH-MB. In contrast, the developmental basis of Group 3/4-MB remains poorly understood, hampering context-relevant mechanistic studies, generation of accurate disease models, and the advancement of molecularly targeted therapies urgently needed to improve patient outcomes. Recent single-cell genomics studies lead by PI Northcott and others have provided initial clues into the putative origins of Group 4-MB, the largest and least characterized MB subgroup, implicating multiple glutamatergic lineages born out of the upper rhombic lip germinal zone. However, these studies failed to confidently identify cerebellar correlates of Group 3-MB, the most clinically challenging MB subgroup. Decoding the interplay between cellular lineages of the developing cerebellum and Group 3/4-MB pathogenesis represents a fundamental challenge in the field and will be the primary objective of this research program. We hypothesize that Group 3/4-MB tumors arise from discrete lineage trajectories during early cerebellar development. Solving the developmental origins of Group 3/4-MB will provide essential knowledge required to (i) investigate context-specific mechanisms of tumorigenesis; (ii) inform preclinical modeling strategies; (iii) identify previously hidden oncogenic drivers; and (iv) illuminate novel therapeutic opportunities. This hypothesis will be tested in three conceptually and technically innovative Specific Aims that integrate a multidisciplinary and multispecies experimental approach. In Aim #1, we will leverage an unprecedented single-cell transcriptional atlas of murine cerebellar development and elegant lineage enrichment strategies to enable cross-species inference of MB subgroup origins and execute context-relevant experimental perturbation of MB driver genes. In Aim #2, we will deliver the first comprehensive investigation of MB cellular origins through the lens of human fetal cerebellar development. These analyses will enlighten species-specific differences in cerebellar development linked to tumorigenesis and foster the discovery of tumor-specific signatures driving malignancy. In Aim #3, we will use focused CRISPR targeting, acute protein degradation, and next-generation synthetic gene regulators to define developmentally linked transcriptional dependencies in high- risk MB. These studies will credential conserved master transcription factors as attractive leads for future therapeutic consideration. Successful execution of this research program will fill an essential knowledge gap associated with the known biological and clinical heterogeneity of Group 3/4-MB and provide a novel direction for the pursuit of more specific, less toxic treatment options for affected children.