Notch Signaling in Brain Development and Cancer

Notch signaling plays an important role in developmental biology and is known to be active in malignant tumors. While the Notch pathway has been extensively studied in both settings, little is known about the role of specific Notch receptors and the differences between them. Moreover, little is known about the potential for therapeutic resistance to drugs targeting the Notch signaling pathway in malignant tumors. Multiple developmental pathways including Notch, Hedgehog, and Wnt are active in malignant brain tumors such as medulloblastoma and glioblastoma (GBM). This raises the possibility that tumors might compensate for therapy directed against one pathway by upregulating other pathways. To assess this, we investigated the effects of Notch inhibition on malignant brain tumors by treating cell lines with a gamma-secretase inhibitor (GSI) or shRNAs against Notch receptors. We observed that our GBM neurosphere cultures continued to grow over long periods of moderate GSI treatment, despite ongoing Notch pathway suppression, suggesting the emergence of resistance to treatment. We identified Gli1 as a novel target of Hes1, and showed that this relationship permits upregulation of Hedgehog signaling when Notch is suppressed. Moreover, targeting both Notch and Hedgehog simultaneously with pharmacologic agents decreased cell growth, colony-forming ability, and induced apoptosis more dramatically than monotherapy. We were able to extend these results to primary GBM tumors, indicating that targeting multiple developmental pathways is more effective than monotherapy at eliminating GBM cells. In addition to investigating the ability of malignant tumors to resist Notch blockade, we investigated the ability of Notch2 to induce tumors of the brain and eye. We found that activated Notch2 is able to induce choroid plexus papillomas, cataracts, and glial lesions when overexpressed during development. This occurred in a fashion unique from Notch1 or Notch3 and suggests the Notch receptors may have differential effects on different cell types. Our findings demonstrate that Notch signaling plays an important role in the initiation and maintenance of brain and eye tumors. Therapeutics against the Notch pathway may prove invaluable, but should be evaluated carefully for the potential of therapeutic resistance