Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells

High-risk neuroblastoma remains one of the deadliest childhood cancers. Identification of metabolic pathways that drive or maintain high-risk neuroblastoma may open new avenues of therapeutic interventions. Here, we report the isolation and propagation of neuroblastoma sphere-forming cells with self-renewal and differentiation potential from tumors of the TH-MYCN mouse, an animal model of high-risk neuroblastoma with MYCN amplification. Transcriptional profiling reveals that mouse neuroblastoma sphere-forming cells acquire a metabolic program characterized by transcriptional activation of the cholesterol and serine-glycine synthesis pathways, primarily as a result of increased expression of sterol regulatory element binding factors and Atf4, respectively. This metabolic reprogramming is recapitulated in high-risk human neuroblastomas and is prognostic for poor clinical outcome. Genetic and pharmacological inhibition of the metabolic program markedly decreases the growth and tumorigenicity of both mouse neuroblastoma sphere-forming cells and human neuroblastoma cell lines. These findings suggest a therapeutic strategy for targeting the metabolic program of high-risk neuroblastoma. [Display omitted] •TH-MYCN mouse neuroblastoma sphere-forming cells are cancer stem-like cells•Their function requires activation of serine and cholesterol synthesis pathways•These metabolic pathway genes are activated in high-risk human neuroblastoma•Metabolic gene expression may be prognostic for neuroblastoma patients Liu et al. examine a common metabolic program for tumorigenicity in TH-MYCN mouse neuroblastoma sphere-forming cells and high-risk human neuroblastoma. The metabolic program is characterized by activation of serine-glycine and cholesterol synthesis genes. These findings suggest possible targets for therapeutic interventions in high-risk neuroblastoma.