Liu Mengling, Xia Yingfeng, Ding Jane, Ye Bingwei, Zhao Erhu, Choi Jeong-Hyeon, Alptekin Ahmet, Yan Chunhong, Dong Zheng, Huang Shuang, Yang Liqun, Cui Hongjuan, Zha Yunhong, Ding Han-Fei
Department of Neurology, Institute of Neural Regeneration and Repair, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, 443000, China.
The Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
Cell Rep. 2016 Oct 4;17(2):609-623. doi: 10.1016/j.celrep.2016.09.021.
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.
高危神经母细胞瘤仍然是最致命的儿童癌症之一。识别驱动或维持高危神经母细胞瘤的代谢途径可能会开辟新的治疗干预途径。在此，我们报告了从TH-MYCN小鼠（一种具有MYCN扩增的高危神经母细胞瘤动物模型）的肿瘤中分离并培养出具有自我更新和分化潜能的神经母细胞瘤成球细胞。转录谱分析显示，小鼠神经母细胞瘤成球细胞获得了一种代谢程序，其特征是胆固醇和丝氨酸-甘氨酸合成途径的转录激活，这主要分别是由于固醇调节元件结合因子和Atf4表达增加所致。这种代谢重编程在高危人类神经母细胞瘤中也有体现，并且预示着临床预后不良。对该代谢程序的基因和药理学抑制显著降低了小鼠神经母细胞瘤成球细胞和人类神经母细胞瘤细胞系的生长和致瘤性。这些发现提示了一种针对高危神经母细胞瘤代谢程序的治疗策略。
