Ptc Deletion in GNPs Leads to Medulloblastoma

Medulloblastoma is often found on the surface of cerebellum, but which cell types give rise to medulloblastoma has been debated for many years. Both cerebellar granule neuron precursors (GNPs) and neural stem cells (NSCs) have been postulated to be the cell of origin for medulloblastoma. To examine the cellular origins for the group of medulloblastomas arising from activating mutations in the Sonic Hedgehog (Shh) pathway, we used transgenic mice (Math1-Cre mice and GFAP-Cre mice) to specifically delete Patched (an inhibitor of the Shh pathway) in GNPs or NSCs, respectively.  Deletion of Patched in GNPs causes medulloblastoma in mice by 3 months of age. Loss of Patched in NSCs promotes stem cell proliferation, but only causes tumors after these cells have committed to a neuronal lineage. Notably, tumors initiated in NSCs develop more rapidly than those initiated in GNPs, with all animals succumbing by 3-4 weeks. These studies suggest that medulloblastoma can be initiated from neuronal progenitors or stem cells, but that Shh-induced tumorigenesis is associated with neuronal lineage commitment.

Most GNPs Differentiate Despite Loss of Ptc

The fact that activation of Shh signalling by Patched deletion in cerebellar GNPs leads to tumors in 100% of mice, suggests that GNPs can represent the cells of origin for medulloblastoma. However, in these animals, only a small percentage of GNPs give rise to the tumor; despite loss of Patched, the remaining GNPs proliferate transiently and then differentiate. This implies that only a subset of GNPs can be transformed by Patched deletion. We are currently working to identify this subset of cells, and determine the molecular basis of their tumorigenicity. Understanding the unique properties of these cells will provide insight into tumorigenesis of medulloblastoma, and allow us to develop more effective methods for treating this highly malignant tumor.

Heterogeneity of the Tumor Tissue

Tumors are far more than a cluster of proliferating cells; they are actually a complex mixture of neoplastic cells and supporting cells, including endothelial cells, fibroblasts, macrophages and other cell types, which are collectively known as stromal cells. Reciprocal interaction between these stromal cells and neoplastic cells result in continued growth, survival and invasion of tumors. In our laboratory, we are examining the interaction between medulloblastoma cells and stromal cells, and identifying the role of stromal cells in the initiation, progression and drug resistance of medulloblastoma.