Osama Aya, Karam Ahmed, Atef Abdelrahman, Arafat Menna, Afifi Rahma W, Mokhtar Maha, Abdelmoneim Taghreed Khaled, Ramzy Asmaa, El Nadi Enas, Salama Asmaa, Elzayat Emad, Magdeldin Sameh
Proteomics and Metabolomics Unit, Basic Research Department, Children's Cancer Hospital (CCHE-57357), Cairo 57357, Egypt.
Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
Cells. 2025 Jul 20;14(14):1115. doi: 10.3390/cells14141115.
Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, comprises embryonal (ERMS) and alveolar (ARMS) subtypes with distinct histopathological features, clinical outcomes, and therapeutic responses. To better characterize their molecular distinctions, we performed untargeted plasma proteomics and metabolomics profiling in children with ERMS ( = 18), ARMS ( = 17), and matched healthy controls ( = 18). Differential expression, functional enrichment (GO, KEGG, RaMP-DB), co-expression network analysis (WGCNA/WMCNA), and multi-omics integration (DIABLO, MOFA) revealed distinct molecular signatures for each subtype. ARMS displayed elevated oncogenic and stemness-associated proteins (e.g., cyclin E1, FAP, myotrophin) and metabolites involved in lipid transport, fatty acid metabolism, and polyamine biosynthesis. In contrast, ERMS was enriched in immune-related and myogenic proteins (e.g., myosin-9, SAA2, S100A11) and metabolites linked to glutamate/glycine metabolism and redox homeostasis. Pathway analyses highlighted subtype-specific activation of PI3K-Akt and Hippo signaling in ARMS and immune and coagulation pathways in ERMS. Additionally, the proteomics and metabolomics datasets showed association with clinical parameters, including disease stage, lymph node involvement, and age, demonstrating clear molecular discrimination consistent with clinical observation. Co-expression networks and integrative analyses further reinforced these distinctions, uncovering coordinated protein-metabolite modules. Our findings reveal novel, subtype-specific molecular programs in RMS and propose candidate biomarkers and pathways that may guide precision diagnostics and therapeutic targeting in pediatric sarcomas.
横纹肌肉瘤（RMS）是最常见的儿童软组织肉瘤，包括胚胎型（ERMS）和肺泡型（ARMS）亚型，具有不同的组织病理学特征、临床结局和治疗反应。为了更好地描述它们的分子差异，我们对患有ERMS（n = 18）、ARMS（n = 17）的儿童以及匹配的健康对照（n = 18）进行了非靶向血浆蛋白质组学和代谢组学分析。差异表达、功能富集（GO、KEGG、RaMP-DB）、共表达网络分析（WGCNA/WMCNA）和多组学整合（DIABLO、MOFA）揭示了每种亚型独特的分子特征。ARMS显示致癌和干性相关蛋白（如细胞周期蛋白E1、FAP、肌养蛋白）以及参与脂质转运、脂肪酸代谢和多胺生物合成的代谢物水平升高。相比之下，ERMS富含免疫相关和肌源性蛋白（如肌球蛋白-9、SAA2、S100A11）以及与谷氨酸/甘氨酸代谢和氧化还原稳态相关的代谢物。通路分析突出了ARMS中PI3K-Akt和Hippo信号的亚型特异性激活以及ERMS中的免疫和凝血通路。此外，蛋白质组学和代谢组学数据集显示与临床参数相关，包括疾病分期、淋巴结受累情况和年龄，表明与临床观察一致的明显分子区分。共表达网络和综合分析进一步强化了这些差异，揭示了协调的蛋白质-代谢物模块。我们的研究结果揭示了RMS中新型的、亚型特异性的分子程序，并提出了可能指导儿童肉瘤精准诊断和治疗靶向的候选生物标志物和通路。
