GDP-mannose 4,6-dehydratase is a key driver of MYCN-amplified neuroblastoma core fucosylation and tumorigenesis

Abstract

MYCN-amplification is a genetic hallmark of ~40% of high-risk neuroblastomas (NBs). Altered glycosylation is a common feature of adult cancer progression, but little is known about how genetic signatures such as MYCN-amplification alter glycosylation profiles. Herein, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased core fucosylated glycan abundance within neuroblast-rich regions of human MYCN-amplified NB tumors. GDP-mannose 4,6-dehydratase (GMDS) is responsible for the first-committed and rate-limiting step of de novo GDP-fucose synthesis. High GMDS expression was found to be associated with poor patient survival, advanced stage disease, and MYCN-amplification in human NB tumors. Chromatin immunoprecipitation and promoter reporter assays demonstrated that N-MYC directly binds and activates the GMDS promoter in NB cells. When GMDS was blocked through either genetic or pharmacological mechanisms, NBs were found to be dependent upon de novo GDP-fucose production to sustain cell surface and secreted core fucosylated glycan abundance, as well as adherence and motility. Moreover, genetic knockdown of GMDS inhibited tumor formation and progression in vivo. These critical findings identify de novo GDP-fucose production as a novel metabolic vulnerability that may be exploited in designing new treatment strategies for MYCN-amplified NBs.