Identify Genetic Drivers Metastasis Using an Established Zebrafish Model of High-Risk Neuroblastoma

Dr. Nicole Anderson, Ph.D. – University of Mississippi Medical Center, Jackson, MS 

Metastatic disease is difficult to treat in neuroblastoma (NB) and is the number one cause of death. Unfortunately, we know little about the mechanisms that control metastasis in NB due to the lack of an appropriate animal model. Patients are designated as high-risk (HR) for having MYCN-amplification or being over 18-months-of-age with metastatic disease. In addition, segmental chromosomal aberrations (SCA) are the most common genetic alteration in HR-NB, where large chromosomal regions are lost or gained disrupting 100s of genes. Determining which genes are critical to metastatic disease within a SCA is difficult, as many are passengers genes that are not important in disease pathology. The zebrafish is important in vivo model for defining the role of new genetic mutations in HR-NB. MYCN_TT zebrafish are unique NB animal model that spontaneously metastasize. Our preliminary data shows that MYCN_TT tumors evolve through copy number alterations (CNA), like HR-NB. We will perform whole genome sequencing to detect CNA in highly metastatic MYCN_TT zebrafish. Next, we will use a cross-species genomics approach to identify CNA shared in both metastatic MYCN_TT and human NB. CNAs shared between species separated by 450 million years of evolution are strong candidate drivers of metastatic disease in NB. Finally, we will test our top 5 driver CNA in human NB cell lines to see their impact on metastatic phenotypes (invasion and migration).