SignificanceHigh-risk neuroblastoma (NB), a cancer of the sympathetic nervous system, is challenging to treat. MYCN is frequently amplified in high-risk NB and is linked to an undifferentiated phenotype and poor prognosis. Estrogen and nerve growth factor (NGF) are inducers of neural differentiation, a process associated with a favorable disease. We show that MYCN suppresses estrogen receptor alpha (ERα) and thereby NGF signaling and neural differentiation. ERα overexpression is sufficient to interfere with different tumorigenic processes and tumor growth. In patients with NB, ERα expression correlates with several clinical markers for good prognosis. Importantly, not only ERα but also the majority of other nuclear hormone receptors are linked to favorable NB, suggesting a potential prognostic and therapeutic value for these proteins.
In this issue of Cancer Research, Xia and colleagues show that MYC-induced metabolic reprograming results in dependency on the serine-glycine-one-carbon (SGOC) metabolic pathway in neuroblastoma. This occurs through MYCN and ATF4 activation of the SGOC biosynthetic pathway in MYCN-amplified cells. Furthermore, inhibition of de novo serine synthesis generates metabolic stress in MYCN-amplified neuroblastoma cells, causing cellcycle arrest and autophagy. Together, these data suggest that the SGOC pathway is an attractive therapy target in neuroblastoma. See related article by Xia et al., p. 3837
Medulloblastoma (MB) is the most common malignant brain tumour in children. High-risk MB patients harbouring MYC amplification or overexpression exhibit a very poor prognosis. Aberrant activation of MYC markedly reprograms cell metabolism to sustain tumorigenesis, yet how metabolism is dysregulated in MYC-driven MB is not well understood. Growing evidence unveiled the potential of BET-bromodomain inhibitors (BETis) as next generation agents for treating MYC-driven MB, but whether and how BETis may affect tumour cell metabolism to exert their anticancer activities remains unknown. In this study, we explore the metabolic features characterising MYC-driven MB and examine how these are altered by BET-bromodomain inhibition. To this end, we employed an NMR-based metabolomics approach applied to the MYC-driven MB D283 and D458 cell lines before and after the treatment with the BETi OTX-015. We found that OTX-015 triggers a metabolic shift in both cell lines resulting in increased levels of myo-inositol, glycerophosphocholine, UDP-N-acetylglucosamine, glycine, serine, pantothenate and phosphocholine. Moreover, we show that OTX-015 alters ascorbate and aldarate metabolism, inositol phosphate metabolism, phosphatidylinositol signalling system, glycerophospholipid metabolism, ether lipid metabolism, aminoacyl-tRNA biosynthesis, and glycine, serine and threonine metabolism pathways in both cell lines. These insights provide a metabolic characterisation of MYC-driven childhood MB cell lines, which could pave the way for the discovery of novel druggable pathways. Importantly, these findings will also contribute to understand the downstream effects of BETis on MYC-driven MB, potentially aiding the development of new therapeutic strategies to combat medulloblastoma.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.