Notch1 switches progenitor competence in inducing medulloblastoma

The identity of the cell of origin is a key determinant of cancer subtype, progression, and prognosis. Group 3 medulloblastoma (MB) is a malignant childhood brain cancer with poor prognosis and few candidates as putative cell of origin. We overexpressed the group 3 MB genetic drivers MYC and Gfi1 in different candidate cells of origin in the postnatal mouse cerebellum. We found that S100b⁺ cells are competent to initiate group 3 MB, and we observed that S100b⁺ cells have higher levels of Notch1 pathway activity compared to Math1⁺ cells. We found that additional activation of Notch1 in Math1⁺ and Sox2⁺ cells was sufficient to induce group 3 MB upon MYC/Gfi1 expression. Together, our data suggest that the Notch1 pathway plays a critical role in group 3 MB initiation.