MYCN and Metabolic Reprogramming in Neuroblastoma

SIMPLE SUMMARY: Metabolic reprogramming has a central role in the initiation and progression of cancer, including high-risk neuroblastoma, a deadly childhood malignant tumor of the sympathetic nervous system. This rewiring of cellular metabolism increases the manufacture of fuel and building blocks for biomass production, which is essential to sustain the growth and proliferation of neuroblastoma cells. However, the rewiring also makes neuroblastoma cells metabolically distinct from normal sympathetic neurons, thereby offering new therapeutic opportunities. In this review, we summarize the recent progress in the study of neuroblastoma metabolic reprogramming and underlying molecular mechanisms. ABSTRACT: Neuroblastoma is a pediatric cancer responsible for approximately 15% of all childhood cancer deaths. Aberrant MYCN activation, as a result of genomic MYCN amplification, is a major driver of high-risk neuroblastoma, which has an overall survival rate of less than 50%, despite the best treatments currently available. Metabolic reprogramming is an integral part of the growth-promoting program driven by MYCN, which fuels cell growth and proliferation by increasing the uptake and catabolism of nutrients, biosynthesis of macromolecules, and production of energy. This reprogramming process also generates metabolic vulnerabilities that can be exploited for therapy. In this review, we present our current understanding of metabolic reprogramming in neuroblastoma, focusing on transcriptional regulation as a key mechanism in driving the reprogramming process. We also highlight some important areas that need to be explored for the successful development of metabolism-based therapy against high-risk neuroblastoma.