Metastasis is the primary cause of mortality in Neuroblastoma (NB) patients, but the metastatic process in NB is poorly understood. Metastsis is a multistep process that requires the coordinated action of many genes. The identification of genes that promote or suppress tumor metastasis can advance our understanding of this process. In the present study, we utilized a human NB xenograft model comprising local and metastatic NB variants, which was recently developed in our laboratory. We set out to identify molecular correlates of NB metastasis and to determine the clinical relevance of these molecules. We first performed genome-wide expression profiles of metastatic and nonmetastatic NB variants that have an identical genetic background. We found that some of the proteins highly expressed in the metastatic NB variants are localized in the cytoplasm and endoplasmic reticulum. Other proteins are linked to metabolic processes and signaling pathways, thereby supporting the invasive and metastatic state of the cells. Subsequently, we intersected the differentially expressed genes in the human xenografted variants with genes differentially expressed in Stage 1 and Stage 4 primary tumors of NB patients. By using the same gene-expression platform, molecular correlates associated with metastatic progression in primary NB tumors were identified. The resulting smaller gene set was clinically relevant as it discriminated between high-and low-risk NB patients.Neuroblastoma (NB) is the most commonly occurring extracranial tumor in childhood. These tumors originate in embryonic neural crest precursor cells of the sympathetic nervous system. NB accounts for $8% of all malignancies in patients younger than 15 years, and occurs most frequently in the adrenal gland. 1 The tumors can regress spontaneously, particularly in infants. However, children older than 1 year of age, with a widespread metastatic disease or with a large, aggressive, localized tumor, have a poor long-term survival rate of $30%. 2,3 Metastasis is the primary cause of mortality in cancer patients, but despite of that it is one of the most poorly understood processes in cancer biology. This is a multistep process that requires the coordinated action of many genes. [4][5][6] A systematic identification of genes that promote or suppress tumor invasion and metastasis can advance the understanding of this process.We recently described the generation and characterization of novel local and metastatic human NB variants. 7 Lungmetastasizing MHH-NB-11 cells were isolated from mice bearing orthotopically inoculated adrenal tumors. ''Local'' variants were isolated from the adrenal tumors. ''Lung metastatic'' variants were generated by repeated cycles of in vivo passages. These cells displayed an aggressive and metastatic phenotype in vivo, portend a poor prognosis and exhibited unique properties in vitro. 7 Oberthuer et al. recently described a robust, gene-expression-based classifier, which reliably predicts NB tumor behavior and can aid physicians in choosing the most app...