Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells
Mengling Liu,
Yingfeng Xia,
Jane Ding,
Bingwei Ye,
Erhu Zhao,
Jeong-Hyeon Choi,
Ahmet Alptekin,
Chunhong Yan,
Zheng Dong,
Shuang Huang,
Liqun Yang,
Hongjuan Cui,
Yunhong Zha,
Han-Fei Ding
Affiliations
Mengling Liu
Department of Neurology, Institute of Neural Regeneration and Repair, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, 443000, China
Yingfeng Xia
Department of Neurology, Institute of Neural Regeneration and Repair, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, 443000, China
Jane Ding
The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Bingwei Ye
The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Erhu Zhao
State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China
Jeong-Hyeon Choi
The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Ahmet Alptekin
The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Chunhong Yan
The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Zheng Dong
The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Shuang Huang
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32611, USA
Liqun Yang
State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China
Hongjuan Cui
State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400715, China
Yunhong Zha
Department of Neurology, Institute of Neural Regeneration and Repair, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, 443000, China
Han-Fei Ding
The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
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.
