Chen Kai,Wu Zhixiang,Wu Yeming.Proteomic profiling-based clinical risk analysis and molecular subtypic identification in neuroblastoma[J].Journal of Clinical Pediatric Surgery,,():316-322.[doi:10.3760/cma.j.cn101785-20251228-00138]
Proteomic profiling-based clinical risk analysis and molecular subtypic identification in neuroblastoma
- Abstract:
- Objective Neuroblastoma (NB) is characterized by profound clinical heterogeneity.Current clinical indicators have failed to fully elucidate its complex biological nature.This study was intended to utilize in-depth proteomic analysis to resolve the molecular features of NB,refine risk stratifications and identify potential therapeutic targets.Methods A cohort of 150 NB children was enrolled for deep characterization using high-throughput quantitative proteomics.Molecular differences across different clinical risk levels (high/intermediate/low risk) and primary sites (adrenal vs non-adrenal) were examined via supervised clustering.Unsupervised clustering was applied for defining proteomic subtypes.And metabolic dependency of high-risk subtypes was validated through cellular experiments using such a metabolic inhibitor as Etomoxir.Results Proteomic expression profiling hinted at high consistency with clinical risk stratification.The high-risk group was significantly enriched in oxidative phosphorylation,MYC targets,E2F targets and DNA repair pathways while the low-risk group exhibited stronger features of epithelial-mesenchymal transition (EMT) and differentiation.Adrenal-derived tumors demonstrated a significantly worse prognosis as compared to non-adrenal-derived tumors.The former was enriched with MYC signaling,oxidative phosphorylation and embryonic development-related proteins,reflecting a dedifferentiated state; the latter was characterized by obvious immune activation (complement and humoral immunity).Unsupervised clustering categorized NB into four distinct subtypes.PAM1 (stromal-type): Excellent prognosis and enrichment of extracellular matrix proteins.PAM2 (splicing-type): Characterized by RNA processing activation.PAM3 (immune-type): High death risk due to immune escape despite lymphocyte infiltration.PAM4 (metabolic-type): The worst prognosis and extremely active energy metabolism.Experimental validation confirmed that NB cells were specifically sensitive to fatty acid oxidation (FAO) inhibitor Etomoxir,significantly suppressing cell viability,indicating a high reliance of PAM4 subtype on mitochondrial energy metabolism.Conclusions This study constructs a proteomic molecular landscape of neuroblastoma and proposes a precise four-subtype molecular model.Our findings reveal the embryonic features of adrenal-origin tumors and pinpoint the metabolic dependency of ultra-high-risk subtype (PAM4) on fatty acid oxidation.These results provide theoretical and experimental rationales for precision stratification and mitochondrial metabolism-targeted therapy for NB.
References:
[1] 张梅慧, 姜大朋.先天性神经母细胞瘤发病机制与临床特点的研究进展[J].临床小儿外科杂志, 2022, 21(2):141-145.DOI:10.3760/cma.j.cn101785-202105045-008. Zhang MH, Jiang DP.Pathogenesis and clinical characteristics of congenital neuroblastoma[J].DOI:10.3760/cma.j.cn101785-202105045-008.
[2] Maris JM.Recent advances in neuroblastoma[J].N Engl J Med, 2010, 362(23):2202-2211.DOI:10.1056/NEJMra0804577.
[3] Khelifa L, Hu YB, Tall J, et al.Diagnostic technologies for neuroblastoma[J].Lab Chip, 2025, 25(15):3630-3664.DOI:10.1039/d4lc00005f.
[4] Cohn SL, Pearson ADJ, London WB, et al.The International Neuroblastoma Risk Group (INRG) classification system: an INRG task force report[J].J Clin Oncol, 2009, 27(2):289-297.DOI:10.1200/JCO.2008.16.6785.
[5] Pugh TJ, Morozova O, Attiyeh EF, et al.The genetic landscape of high-risk neuroblastoma[J].Nat Genet, 2013, 45(3):279-284.DOI:10.1038/ng.2529.
[6] Dong R, Yang R, Zhan Y, et al.Single-cell characterization of malignant phenotypes and developmental trajectories of adrenal neuroblastoma[J].Cancer Cell, 2020, 38(5):716-733.e6.DOI:10.1016/j.ccell.2020.08.014.
[7] Blavier L, Yang RM, DeClerck YA.The tumor microenvironment in neuroblastoma: new players, new mechanisms of interaction and new perspectives[J].Cancers (Basel), 2020, 12(10):2912.DOI:10.3390/cancers12102912.
[8] Brady SW, Liu YL, Ma XT, et al.Pan-neuroblastoma analysis reveals age-and signature-associated driver alterations[J].Nat Commun, 2020, 11(1):5183.DOI:10.1038/s41467-020-18987-4.
[9] Wienke J, Dierselhuis MP, Tytgat GAM, et al.The immune landscape of neuroblastoma: challenges and opportunities for novel therapeutic strategies in pediatric oncology[J].Eur J Cancer, 2021, 144:123-150.DOI:10.1016/j.ejca.2020.11.014.
[10] Arif T, Shteinfer-Kuzmine A, Shoshan-Barmatz V.Decoding cancer through silencing the mitochondrial gatekeeper VDAC1[J].Biomolecules, 2024, 14(10):1304.DOI:10.3390/biom14101304.
[11] 龙俊汕, 张京, 苏小霞, 等.儿童神经母细胞瘤靶向治疗的研究进展[J].临床小儿外科杂志, 2023, 22(7):619-624.DOI:10.3760/cma.j.cn101785-202303039-004. Long JS, Zhang J, Su XX, et al.Research advances of targeted therapy for neuroblastoma in children[J].J Clin Ped Sur, 2023, 22(7):619-624.DOI:10.3760/cma.j.cn101785-202303039-004.
[12] Bansal M, Gupta A, Ding HF.MYCN and metabolic reprogramming in neuroblastoma[J].Cancers (Basel), 2022, 14(17):4113.DOI:10.3390/cancers14174113.
Memo
收稿日期:2025-12-28。
基金项目:国家自然科学基金(82472715)
通讯作者:吴晔明,Email:wuymsh@163.com