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.

Neuroblastoma is a devastating pediatric solid tumor that, despite significant recent advances, still accounts for nearly 15% of all childhood cancer deaths. Patients are risk stratified based on a number of features, including amplification of the MYCN oncogene, yet targeting MYCN itself has been unsuccessful to date. The complex interplay between this oncogene and its many metabolic targets has proven challenging and is only beginning to be understood in the context of pediatric tumors. It is increasingly recognized, however, that MYCN-driven metabolic rewiring and concomitant increases in biosynthetic precursors has the potential to drive many aspects of tumor development. Furthermore, emerging research suggests that improving overall therapeutic outcomes for neuroblastoma patients may well require individual metabolic profiling, allowing personalized simultaneous targeting of multiple metabolic nodes. In this review, we outline clinically relevant research involving MYCN-driven metabolic derangements, including increased glucose uptake, polyamine synthesis, glycosylation, and others, and attempt to summarize the influence of MYCN on important metabolic genes and druggable protein targets. We spotlight emerging research in glycosylation and its modulation as an often overlooked but increasingly promising therapeutic area. It is our hope that this document will provide utility for both clinicians and scientists seeking to understand how the MYCN oncogene and metabolism are critically intertwined.

Lung cancer is one of the most prevalent cancers worldwide, accounting for nearly two million new cases each year. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and is the leading cause of cancer related mortalities worldwide. LUAD has an extremely poor five-year survival rate, which is likely due to cases being diagnosed at advanced stages and thus being more difficult to treat the metastatic disease. Identifying the molecular processes that contribute to disease progression is a critical goal in lung cancer research that could lead to predictive biomarkers and novel therapies. Glycogen is the primary form of carbohydrate storage in mammalian cells, and its degradation product, Glucose 6-Phosphate (G6P) feeds directly into glycolysis, making glycogen intimately connected to central carbon metabolism. Recently, aberrant glycogen accumulation in lung tumors has been reported to promote lung cancer progression, driven by largely unknown mechanisms. We recently generated a transgenic KRAS^G12D/p53^-/- LUAD mouse model that also lacks the glycogen phosphatase laforin (LKO). This model develops increased glycogen accumulation in the lungs and displays accelerated tumor growth compared to the KRAS^G12D/p53^-/- control (WT), as measured by Ki67 staining. To identify potential biological processes perturbed by LUAD-glycogen, we performed RNA-seq on lung tumors resected from WT and LKO mice. We identified over 300 genes that are differentially expressed between WT and LKO lung tumors. Specifically, gene set enrichment analysis (GSEA) revealed genes that were upregulated in LKO lung tumors were involved in extracellular matrix remodeling, cell-to-cell communication, and cell proliferation. All of these processes are implicated in tumor growth, which supports our initial observation that LKO mice have increased tumor burden and disease progression. Our findings ultimately highlight several potential mechanisms by which LUAD-glycogen promotes LUAD tumor progression, which can be further investigated to identify novel biomarkers and therapeutic targets. Citation Format: Jessica Faith Lamb, Lindsey R. Conroy, Alexis N. James, Michael D. Buoncristiani, Eric R. Relich, Lindsay E. Young, Christine F. Branson, Ramon C. Sun. Aberrant glycogen accumulation alters gene expression and promotes lung tumor progression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2382.