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. Interestingly, we found that additional activation of Notch1 in Math1+ and Sox2+ cells was sufficient to induce Group 3 MB upon MYC/Gfi1 expression. Taken together, our data suggest that the Notch1 pathway plays a critical role in Group 3 MB initiation. Overall design: RNA-sequencing profiles of medulloblastoma samples induced by N1ICD+MYC/Gfi1 (in Math1+ cells) and MYC/Gfi1 (in S100b+ cells) compared with previously published Group 3 MB mouse models (MYC/Gfi1, MYC/Otx2)