Oncogenic Pathways and Molecular Prognostics in Neuroblastoma

Sammanfattning: Neuroblastoma is an embryonal malignancy that accounts for 15% of all cancer related deaths amongst children. Although the overall survival of patients has been improving over the last decades, the high-risk neuroblastoma patients have a survival rate of <50%.
Using gene expression microarrays we identify a group of proteins (snoRNPs) whose expression correlates with poor prognosis. We futher show that the snoRNPs are involved in regulation of telomerase activity in neuroblastoma cells. Upon snoRNP knockdown there is an observed increase in anaphase bridge fromation, indicitive of elevated genetic instability. Examination of genes associated with good prognosis revealed genes involved in growth cone formation. Combination of the expressoin of growth cone associated genes with the snoRNPs resulted in a 4-gene prognostic signature. Calculating the ratio (R-score) between the expression of the good and bad prognostic genes removed the need for housekeeper normalization, and provided a means of individual patient analysis. Application of a fixed-value R-score to 3 independent cohorts using standard qPCR revealed its functionality on an individual patient basis, as well as identified a subgroup of ulta-high risk patients who could potentially benefit from new treatment modalities.
Amongst high-risk neuroblastomas is a subgroup of patients harbouring MYCN-amplification. Here we show that MCYN-amplified tumours have elevated expression of the miR-17-92 cluster of miRNAs. High-throughput proteomic analysis of miR-17-92 overexpressing cells revealed enrichemnt of the TGF-β pathway. Further analyses showed miR-17-92 targeted inhibition of the TGF-β pathway at multiple levels, resulting in increased tumourigenic capacity of the neuroblastoma cells.
Using primarily breast cancer cells, we identified a hypoxia driven induction of the Notch-ligand JAG2. Deminished expression of JAG2 in hypoxic tumour cells resulted in a reduced capacity of neighbouring endothelial cells to form tubes. Evaluation of these results in neuroblastoma revealed a similar pattern of Notch-ligand dependent crosstalk between tumour and endothelial cells, however in this case with via DLL1.
Here we have investigated, with a focus on high-risk patients, key signalling patways that are involved in the maintenance and progression of the disease. In addition, we describe a novel prognostic signature that has clinical implications for specifically high-risk patients.