Notch Signaling Exhibits a Tumor Suppressor Function in Gliomas

Gliomas are the most common adult brain malignancy and have a poor prognosis, which may be due in part to the presence of a stem-like cell subpopulation that has been shown to be radio- and chemoresistant and to phenotypically resemble neural stem cells (NSC). Although Notch signaling, which is integral for NSC maintenance, has been suggested to play an oncogenic role in some brain tumors, the role of this pathway in glioma remains unclear. Giachino and colleagues interrogated the role of Notch signaling using mouse models of glioma driven by platelet-derived growth factor (PDGF) expression and loss of Trp53 (PDGF⁺/Trp53^−/−) and a reporter mouse in which GFP expression was driven by the promoter of the transcription factor HES5 as a readout of activated Notch signaling. In early-stage PDGF⁺/Trp53^−/− gliomas, HES5 was expressed in only a subpopulation of glioma cells. Targeted expression of PDGF and deletion of Trp53 in HES5⁺ Notch signaling cells resulted in glioma initiation. Surprisingly, deletion of the Notch mediator recombination signal binding protein for immunoglobulin κ J region (Rbpj) accelerated the growth of PDGF⁺/Trp53^−/− gliomas which were mostly composed of HES5⁻ proliferating cells. Late-stage PDGF⁺/Trp53^−/−/Rbpj^−/- gliomas exhibited features of poorly differentiated supratentorial primitive neuroectodermal tumors (sPNET) and proneural/mesenchymal glioblastoma gene signatures. Furthermore, co-deletion of Notch1 and Notch2 in PDGF⁺/Trp53^−/− tumors resulted in accelerated development of malignant glioma, and co-deletion of Rbpj and Trp53 in quiescent NSCs induced the development of premalignant NSCs and highly penetrant sPNET-like tumors. In patients with proneural glioblastoma, HES5 expression was inversely correlated with survival, and the expression of HES5, RBPJ, and the Notch-induced transcription factors HEY1 and HEY2 was associated with better prognosis in grade II and III astrocytomas. Together, these results show that Notch signaling has a tumor-suppressor function in grade II–III astrocytomas, proneural glioblastomas, and sPNETs.

Giachino C, Boulay JL, Ivanek R, Alvarado A, Tostado C, Lugert S, et al. A tumor suppressor function for Notch signaling in forebrain tumor subtypes. Cancer Cell 2015 Dec 5 [Epub ahead of print].