Identification Of Neuroblastoma Metastasis Associated Genes

Metastatic relapse is the major cause of death in neuroblastoma (NB), yet there are no therapies to specifically target metastases. To understand the molecular mechanisms mediating NB metastasis, we developed a mouse model using intracardiac injection and in vivo selection to isolate metastatic subpopulations that exhibited a higher propensity for bone and central nervous system metastases. Gene expression profiling revealed two distinct subtypes, primary and metastatic, with differential regulation of 412 genes and multiple pathways including CADM1, SPHK1, and YAP/TAZ whose expression independently predicted survival. Loss- and gain-of-function experiments with these genes demonstrated a rescue of metastatic phenotypes in multiple NB cell lines in vitro or in vivo. Treatment with the compounds SKI II and Verteporfin that target SPHK1 and YAP/TAZ, respectively, inhibited NB metastasis in vivo. In addition, using gene expression profiling from the metastatic subpopulations, a gene signature (MET-75) was identified that predicts NB survival of patients with metastatic disease. This model therefore identifies genes regulating metastasis and candidate therapeutics for metastatic NB We analysed 16 samples, 4 representing primary NB models and 12 representing metastatic NB models.