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Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma
Mengling Liu1, Yingfeng Xia1, Jane Ding2
1Department of Neurology, Institute of Neural Regeneration and Repair, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, 443000, China.
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.
Insights
Targeting metabolic pathways in high-risk neuroblastoma, a deadly childhood cancer, shows promise. Inhibiting cholesterol and serine-glycine synthesis significantly reduced tumor growth and tumorigenicity in preclinical models.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- High-risk neuroblastoma is a fatal pediatric cancer with limited therapeutic options.
- Understanding the metabolic drivers of neuroblastoma is crucial for developing new treatments.
Purpose of the Study:
- To identify and characterize metabolic pathways essential for high-risk neuroblastoma.
- To evaluate the therapeutic potential of targeting these metabolic pathways.
Main Methods:
- Isolation and propagation of neuroblastoma sphere-forming cells from TH-MYCN mouse model.
- Transcriptional profiling to identify metabolic gene expression changes.
- Genetic and pharmacological inhibition of key metabolic pathways.
Main Results:
- Neuroblastoma sphere-forming cells exhibit activated cholesterol and serine-glycine synthesis pathways.
- This metabolic reprogramming is driven by sterol regulatory element binding factors and Atf4.
- Metabolic reprogramming is present in human high-risk neuroblastomas and correlates with poor prognosis.
- Inhibition of these pathways reduced tumor cell growth and tumorigenicity.
Conclusions:
- Metabolic reprogramming, specifically involving cholesterol and serine-glycine synthesis, is a key feature of high-risk neuroblastoma.
- Targeting this metabolic program offers a potential therapeutic strategy for treating high-risk neuroblastoma.
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