Integration of human and mouse single-cell transcriptomes of the developing cerebellum nominates cells-of-origin for Group 3 and 4 medulloblastoma

The cerebellar rhombic lip neurogenic niche is critical for glutamatergic neurogenesis, and dysregulated differentiation of rhombic lip lineage cells is hypothesized to cause medulloblastoma (MB), a malignant pediatric cancer lacking targeted therapies. Humans have an expanded rhombic lip subventricular zone compartment not seen in mice or macaques, and the common Group 4 subtype of MB is hypothesized to arise by dysregulation of the EOMES+ unipolar brush cells (UBC) generated by this compartment. However, it is unknown whether humans have unique UBC populations not seen in the mouse and, if so, whether Group 4 MB tumour cells resemble these UBC populations. We integrated 336,598 human and mouse single-cell transcriptomes of the developing cerebellum (9-21 post-conception weeks in humans and E10-P14 in mice) and identified two subpopulations of UBC that are enriched in the human samples, relative to mice. One of these populations, which we term UBC 1, predominates at 11 post-conception weeks, shows upregulation of the Eyes Shut Homolog (EYS) transcript, is predicted to be driven by OTX2, SOX4, and SOX11, and is enriched for axonogenesis and neurodifferentiation pathways. We analyzed 27,735 single-cell transcriptomes from eight MB tumours and recapitulated the observation that Group 4 MB cells best resemble UBC. We then found that two-thirds of Group 3 and Group 4 MB UBC-like cells best resemble human-enriched UBC 1 cells. Gene regulatory network analysis revealed that top regulators of Group 4 MB tumour cells include EOMES, SOX4, and SOX11. Our work provides initial evidence for human-enriched UBC states, and suggests that SOX4 and SOX11 may drive neurogenesis in UBC and gene expression in a subset of Group 4 MB tumour cells. Our findings shed light on genetic determinants of human cerebellar expansion and suggest that human models may be needed to recapitulate the oncogenesis of Group 3 and 4 MB.