One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the oncogene. However, only a limited number of regulatory proteins that contribute to this complex -mediated process have been elucidated. Here we show that the ( ) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. expression was also suppressed in -amplified neuroblastoma lacking 17p deletion. deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of . Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with overexpression identified that deficiency led to (i) downregulation of genes involved in cell-cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of overexpression. SIGNIFICANCE: Heterozygous deletion or -mediated repression of in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma. .