title: Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells.
abstract: 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.
authors.affiliation: Department of Neurology, Institute of Neural Regeneration and Repair, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, 443000, China.
authors.forename: Mengling
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Neurology, Institute of Neural Regeneration and Repair, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, 443000, China.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Ding
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
authors.forename: Bingwei
authors.initials: B
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China.
authors.forename: Erhu
authors.initials: E
authors.lastname: Zhao
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Alptekin
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Yan
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Cell Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32611, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Neurology, Institute of Neural Regeneration and Repair, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, 443000, China. Electronic address: yzha7808@ctgu.edu.cn.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Zha
authors.affiliation: The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Electronic address: hding@augusta.edu.
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: C081452:Atf4 protein, mouse; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D051779:Sterol Regulatory Element Binding Proteins; D051701:Activating Transcription Factor 4; D014446:Tyrosine 3-Monooxygenase
keywords: MYCN; TH-MYCN mouse; cancer metabolism; cholesterol biosynthesis; high-risk neuroblastoma; mevalonate pathway; neuroblastoma stem cells; serine-glycine biosynthesis; statin