Notch1 switches progenitor competence in inducing medulloblastoma

Summary 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 unknown 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, while Math1 + , Sox2 + or Ascl1 + cells are not. We noted that S100b + cells have higher levels of Notch1 pathway activity compared to Math1 + cells. Interestingly, we found that additional activation of Notch1 in Math1 + cells was sufficient to induce Group 3 MB upon MYC/Gfi1 expression. Taken together, our data suggest that the MB cell of origin competence depends on the cellular identity, which relies on Notch1 activity. Graphical Abstract