In Vivo Analysis of Early Neuroblastoma Development using Transgenic Quail
Neuroblastoma is a pediatric, often fatal tumor of the peripheral nervous system derived from embryonic neural crest cells that fail to properly migrate and differentiate. Advances in genomic profiling of human neuroblastoma patient-derived tissues have identified a correlation between high expression of some neural crest developmental genes and aggressive neuroblastoma. What remains unclear is how critical developmental signaling pathways are mis-regulated, due to a lack of models that permit the study of normal sympathoadrenal lineage to neuroblastoma pathogenesis.
We plan to leverage our expertise in neural crest biology and state-of-the-art in vivo imaging to address this roadblock. We recently discovered a critical role for TrkB signaling during sympathetic nervous system development; high TrkB expression has been correlated with poor prognosis. Here, we propose to study the critical signaling events of TrkB during proper sympathetic neurogenesis and early neuroblastoma pathogenesis. We will test the hypothesis that TrkB signals regulate the plasticity and invasive ability of the neural crest at a critical time period when the early transformation from normal neuroblast to neuroblastoma occurs. Second, we propose to develop an embryonic quail transplantation model that will allow us to study individual human neuroblastoma cell behavioral and genomic changes after transplantation into the embryonic neural crest microenvironment. By studying changes in TrkB expression and other signaling pathways and comparing this with genomic signatures obtained from human patient-derived neuroblastoma tissue, we will be able to rapidly establish and evaluate personalized targeted therapies.