Paret Claudia, Wingerter Arthur, Seidmann Larissa, Ustjanzew Arsenij, Sathyamurthy Shobha, Ludwig Jannis, Schwickerath Philipp, Brignole Chiara, Pastorino Fabio, Wagner Saskia, El Malki Khalifa, Roth Wilfried, Sandhoff Roger, Faber Jörg
Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Helmholtz-Institute for Translational Oncology Mainz (HI-TRON), 55131 Mainz, Germany.
Int J Mol Sci. 2025 Aug 29;26(17):8431. doi: 10.3390/ijms26178431.
High-risk (HR) neuroblastoma (NBL) patients often receive standardized treatment despite wide variations in clinical outcomes, underscoring the need for improved stratification tools. A distinguishing feature of NBL is the patient-specific expression of gangliosides (GGs), particularly GD2, which may serve as biomarkers. We analyzed GG profiles in 18 patient-derived tumors and 11 NBL cell lines using thin-layer chromatography and mass spectrometry. Expression of 0-, a-, and b-series GGs was examined and correlated with clinical risk, outcome, and gene expression data. Low-risk (LR) tumors expressed higher levels of complex b-series GGs. In HR tumors, five GG profiles (A-E) were identified. Profile A featured complex b-series GGs; B showed GD2 dominance; C showed synthesis arrest at GM3 or GD3 due to low expression of the GM2/GD2 synthase, encoded by the gene; D included complex a- and b-series GGs; and E was marked by GM2 and GD1a prevalence. expression served as a prognostic marker. Relapsed tumors following anti-GD2 therapy typically exhibited reduced GD2 levels, except for one profile A tumor that displayed a ceramide anchor shorter than those found in LR tumors. Astonishingly, the ceramide anchor composition of GD2 itself appears to separate LR and HR NBL, hinting at a role of ceramide synthases in NBL biology. All cell lines expressed GM2, but exhibited very low levels of complex b-series GGs. Profile C was found only in cell lines of the mesenchymal subtype. These findings support further investigation of GG composition and associated enzyme expression as potential biomarkers for risk stratification and treatment response in NBL.
高危（HR）神经母细胞瘤（NBL）患者通常接受标准化治疗，尽管临床结果差异很大，这突出了改进分层工具的必要性。NBL的一个显著特征是神经节苷脂（GGs）的患者特异性表达，特别是GD2，它可能作为生物标志物。我们使用薄层色谱法和质谱法分析了18例患者来源的肿瘤和11种NBL细胞系中的GG谱。检测了零系列、a系列和b系列GGs的表达，并将其与临床风险、结果和基因表达数据相关联。低危（LR）肿瘤表达较高水平的复杂b系列GGs。在HR肿瘤中，鉴定出五种GG谱（A-E）。谱A以复杂b系列GGs为特征；B显示GD2占主导地位；C由于由 基因编码的GM2/GD2合酶低表达而显示在GM3或GD3处合成停滞；D包括复杂a系列和b系列GGs；E以GM2和GD1a普遍存在为特征。 表达作为一种预后标志物。抗GD2治疗后复发的肿瘤通常显示GD2水平降低，除了一个谱A肿瘤，其神经酰胺锚比LR肿瘤中的短。令人惊讶的是，GD2本身的神经酰胺锚组成似乎将LR和HR NBL分开，这暗示神经酰胺合酶在NBL生物学中的作用。所有细胞系均表达GM2，但复杂b系列GGs水平极低。仅在间充质亚型的细胞系中发现谱C。这些发现支持进一步研究GG组成和相关酶表达，作为NBL风险分层和治疗反应的潜在生物标志物。
