Notch1 switches progenitor competence in inducing medulloblastoma

Claudio Ballabio; Matteo Gianesello; Chiara Lago; Konstantin Okonechnikov; Marica Anderle; Giuseppe Aiello; Francesco Antonica; Tingting Zhang; Francesca Gianno; Felice Giangaspero; Bassem A Hassan; Stefan M Pfister; Luca Tiberi

doi:10.1126/sciadv.abd2781

Notch1 switches progenitor competence in inducing medulloblastoma

Sci Adv. 2021 Jun 23;7(26):eabd2781. doi: 10.1126/sciadv.abd2781. Print 2021 Jun.

Authors

Claudio Ballabio¹, Matteo Gianesello¹, Chiara Lago¹, Konstantin Okonechnikov^{2

3}, Marica Anderle¹, Giuseppe Aiello¹, Francesco Antonica¹, Tingting Zhang⁴, Francesca Gianno^{5

6}, Felice Giangaspero^{5

6}, Bassem A Hassan⁴, Stefan M Pfister^{2

3

7}, Luca Tiberi⁸

Affiliations

¹ Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy.
² Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
³ Division of Pediatric Neurooncology, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
⁴ Paris Brain Institute-Institut du Cerveau, Sorbonne Université, Inserm, CNRS, Hôpital Pitié-Salpêtrière, 8, Paris, France.
⁵ Dept. of Radiologic, Oncologic and Anatomo Pathological Sciences, University Sapienza of Rome, Rome, Italy.
⁶ IRCCS Neuromed, Pozzilli, Isernia, Italy.
⁷ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
⁸ Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy. luca.tiberi@unitn.it.

Abstract

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.

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