In vivo Analysis of Neuroblastoma Pathogenesis using Transgenic Zebrafish

Neuroblastoma (NB) is an embryonic tumor of the nervous system accounting for approximately 15% of all childhood cancer deaths.  High-risk neuroblastomas often worsen despite intensive chemotherapy and relapse is common and almost uniformly fatal.  A major problem in being able to treat this childhood disease stems from the heterogeneity of the genetic abnormalities that underlie it, which result in a multitude of disease subtypes that make its treatment enormously difficult.  The latest technological breakthroughs that led to the sequencing of the human genome, now allow us to identify many of potential genetic abnormalities in patients with NB.  However, determining which of these hundreds of possibilities are critical and really contribute to the disease requires their rigorous testing in different combinations in amenable animal models.  We recently developed a new zebrafish model of neuroblastoma that recapitulates the features of human NB and have shown for the first time that it can be used to test whether any of these genetic abnormalities contributes to make the disease occur sooner in the living animal.  Because zebrafish are small and reproduce at such high rates, we are able to test many different combinations in a relatively short amount of time, thus making it feasible to identify these critical genetic abnormalities.  The identification of these underlying genetic defects and pathways is the first step to the development of specific therapies to treat the many specific subtypes of this devastating disease.