TP A2

Mouse modeling and crossspecies analysis to optimize identification and targeting of MYCN co-drivers in NB

We and others have shown that MYCN-amplified NBs often harbor additional oncogenic mutations that activate ALK, the RAS pathway, the YAP1 pathway or functionally inactivate TP53, both in primary and relapse NBs. Mutations co-occurring with MYCN amplification may functionally converge on certain pathways or mechanistic principles, and could be essential partners in driving tumorigenesis in high-risk NBs. The molecular complexity of human NBs has hampered investigation of such principles using existing datasets. As such, designing the optimal targeted treatment for tumors co-driven by the strong oncogene, MYCN, and co-occurring oncogenic mutations remains difficult. We have established transgenic mice that conditionally overexpress MYCN in the neural crest and develop NBs at a high incidence. Analyses of chromosomal aberrations and gene expression in these tumors demonstrate that they closely molecularly model human NBs. Since functionally important aberrations are likely to be conserved between species, we plan to use crossspecies analysis of high-throughput data from murine and human NBs to identify aberrations having the highest functional relevance. Tumors derived from our mouse models have proven to be genomically and molecularly less heterogeneous than human NBs. Thus, we anticipate identification of a finite set of commonly affected pathways and combinatorial rules of aberrations co-occuring with MYCN amplification.