原理:代谢的协同重编程主导神经母细胞瘤(NB)的进展。基于阐明代谢重编程的分子机制,开发具有分层指导的NB治疗选择的个性化风险预测方法具有重要的临床意义。方法:采用基于机器学习的多步骤程序,在单细胞和代谢物通量维度阐明了代谢重编程驱动NB恶性进展的协同机制.随后,我们开发了一种有前景的代谢重编程相关预后特征(MPS)和基于MPS分层的个体化治疗方法,并使用临床前模型进行了进一步独立验证.结果:MPS鉴定的MPS-INB显示出明显高于MPS-II对应物的代谢重编程活性。与目前的临床特征相比,MPS显示出更高的准确性[AUC:0.915vs.0.657(MYCN),0.713(INSS阶段),和0.808(INRG分层)]预测预后。AZD7762和依托泊苷被确定为针对MPS-I和IINB的有效治疗剂,分别。随后的生物学测试表明AZD7762基本上抑制了生长,迁移,MPS-INB细胞的侵袭,比MPS-II细胞更有效。相反,依托泊苷对MPS-Ⅱ型NB细胞有较好的治疗作用。更令人鼓舞的是,AZD7762和依托泊苷显著抑制体内皮下肿瘤发生,扩散,MPS-I和MPS-II样本中的肺转移,分别;从而延长荷瘤小鼠的生存期。机械上,AZD7762和依托泊苷诱导的MPS-I和MPS-II细胞凋亡,分别,通过线粒体依赖性途径;MPS-INB通过谷氨酸代谢成瘾和乙酰辅酶A抵抗依托泊苷诱导的细胞凋亡。MPS-INB进展受多种代谢重编程驱动因素的推动,包括多药耐药,免疫抑制和促进肿瘤的炎症微环境。免疫学,MPS-INB通过MIF和THBS信号通路抑制免疫细胞。代谢,MPS-INB细胞的恶性增殖得到了重新编程的谷氨酸代谢的显著支持,三羧酸循环,尿素循环,等。此外,MPS-INB细胞表现出独特的肿瘤促进发育谱系和自我沟通模式,通过发育和自我通讯激活的致癌信号通路增强证明了这一点。结论:本研究为代谢重编程介导的NB恶性进展的分子机制提供了深刻的见解。它还揭示了在新的精确风险预测方法的指导下开发靶向药物,这可能有助于明显改善NB的治疗策略。
Rationale: Synergic reprogramming of metabolic dominates neuroblastoma (NB) progression. It is of great clinical implications to develop an individualized risk prognostication approach with stratification-guided therapeutic options for NB based on elucidating molecular mechanisms of metabolic reprogramming. Methods: With a machine learning-based multi-step program, the synergic mechanisms of metabolic reprogramming-driven malignant progression of NB were elucidated at single-cell and metabolite flux dimensions. Subsequently, a promising metabolic reprogramming-associated prognostic signature (MPS) and individualized therapeutic approaches based on MPS-stratification were developed and further validated independently using pre-clinical models. Results: MPS-identified MPS-I NB showed significantly higher activity of metabolic reprogramming than MPS-II counterparts. MPS demonstrated improved accuracy compared to current clinical characteristics [AUC: 0.915 vs. 0.657 (MYCN), 0.713 (INSS-stage), and 0.808 (INRG-stratification)] in predicting prognosis. AZD7762 and etoposide were identified as potent therapeutics against MPS-I and II NB, respectively. Subsequent biological tests revealed AZD7762 substantially inhibited growth, migration, and invasion of MPS-I NB cells, more effectively than that of MPS-II cells. Conversely, etoposide had better therapeutic effects on MPS-II NB cells. More encouragingly, AZD7762 and etoposide significantly inhibited in-vivo subcutaneous tumorigenesis, proliferation, and pulmonary metastasis in MPS-I and MPS-II samples, respectively; thereby prolonging survival of tumor-bearing mice. Mechanistically, AZD7762 and etoposide-induced apoptosis of the MPS-I and MPS-II cells, respectively, through mitochondria-dependent pathways; and MPS-I NB resisted etoposide-induced apoptosis by addiction of glutamate metabolism and acetyl coenzyme A. MPS-I NB progression was fueled by multiple metabolic reprogramming-driven factors including multidrug resistance, immunosuppressive and tumor-promoting inflammatory microenvironments. Immunologically, MPS-I NB suppressed immune cells via MIF and THBS signaling pathways. Metabolically, the malignant proliferation of MPS-I NB cells was remarkably supported by reprogrammed glutamate metabolism, tricarboxylic acid cycle, urea cycle, etc. Furthermore, MPS-I NB cells manifested a distinct tumor-promoting developmental lineage and self-communication patterns, as evidenced by enhanced oncogenic signaling pathways activated with development and self-communications. Conclusions: This study provides deep insights into the molecular mechanisms underlying metabolic reprogramming-mediated malignant progression of NB. It also sheds light on developing targeted medications guided by the novel precise risk prognostication approaches, which could contribute to a significantly improved therapeutic strategy for NB.