The Molecular Basis of Medulloblastoma: Interaction of Hedgehog and Notch Signalling in Brain Development and Cancer

Brain tumours comprise about 25% of all cancers in children. Medulloblastoma – which arise in the cerebellum – are the most common and severe malignant pediatric brain tumour and the leading cause of cancer-related deaths in children under the age of 9. Treatment of medulloblastoma remains conventional, with surgery followed by chemotherapy and radiation. These measures are successful in about 60-80% of cases but treatment results in severe side effects due to its toxicity to the central nervous system. Therefore it is of utmost importance to define the signalling pathways and genetic changes involved in the formation of medulloblastoma in order to allow for better diagnosis and treatments with higher efficiency and decreased toxicity. The cell of origin for medulloblastoma is thought to be the granule neuron progenitor, a cell type arising from cerebellar stem cells of the ventricular zone. After birth granule neuron progenitors differentiate into mature granule neurons which populate the majority of the cerebellum and are crucial for its cognitive functions and motor coordination. The Hedgehog signalling pathway plays an important role in medulloblastoma generation and murine models with activated Hedgehog signalling develop medulloblastoma at high frequencies. In addition, the Notch pathway has been implicated in the generation of medulloblastoma, and interaction between the two pathways has been suggested. Inhibitors of both Hedgehog and Notch are currently in clinical trials however knowledge of possible interactions between them could lead to more effective treatment strategies. The aim of this project was to investigate the interaction of Hedgehog and Notch signalling in normal brain development and medulloblastoma. Two mouse models allowed activation of Hedgehog and inactivation of Notch signalling in granule neuron progenitors and cerebellar ventricular zone stem cells. In granule neuron progenitors canonical Notch signalling is not required and the layering and cell types of RBP-Jlox/lox;Math1-Cre cerebella appear identical to control brains. In contrast, Notch inactivation in ventricular zone stem cells with GFAP-Cre resulted in increased differentiation of stem cells into progenitor cells accompanied by an overall developmental delay in neuronal differentiation. Medulloblastoma generated by Hedgehog activation (through inactivation of the negative Hedgehog regulator Ptc1) in both cell types cannot be blocked by Notch inactivation. Furthermore, medulloblastoma of Ptc1lox/lox;RBP-Jlox/lox;GFAP-Cre and those of Ptc1lox/lox;RBP-Jlox/lox;Math1-Cre mice are identical in incidence as well as histology to the tumours in which only Hedgehog signalling is activated. This implies that even though Notch signalling plays an important role in cerebellar stem cells it is not required for the initiation and development of Hedgehog induced medulloblastoma. Therefore it may be crucial to consider the Hedgehog status of patients in order to interpret clinical data of Notch pathway inhibitors and even more importantly these results suggest that determining the Hedgehog status might be crucial before treatment of medulloblastoma patients with Notch pathway inhibitors