Differential gene expression analysis of genes deregulated in Ptch1+/+/Tis21 knockout vs. Ptch1+/+/Tis21 wild-type mice

We generated a new medulloblastoma model by crossing Patched1 heterozygous mice, which develop medulloblastomas with low frequency, with mice lacking the Tis21 gene. Double knock-out mice show a significant increase in medulloblastoma frequency and hyperplastic EGL lesions formed by preneoplastic GCPs. We found that Tis21 deletion does not affect the proliferation of GCPs but it inhibits their differentiation and their ability to migrate outside the EGL, remaining for a prolonged time in the cerebellum proliferative area. We identified as a drug target and major responsible of this migration defect the down-regulation of the promigratory chemokine Cxcl3 rather than a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, and focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets. Among them, we identified the activation of the PI3K/AKT/mTOR pathway that contributes to medulloblastoma development and to high frequency tumorigenesis when the Tis21 gene is down-regulated. Moreover, we used a novel PI3K inhibitor in nodules derived from primary Ptch1+/−/Tis21KO causing a significant reduction of tumor growth, inhibiting proliferation and increasing apoptosis. Two-condition experiment, cerebellar granule +precursor cells (GCPs) of Ptch1+/+/Tis21 knockout vs. Ptch1+/+/Tis21 wild-type mice isolated at P7, for each genotype were used three biological replicates.