Wu Zhengjie, Liu Zhiping, Wang Yukun, Teng Geling, Li Xiaodong, Lu Tong, Hu Fangning, Wu Shuo, Ma Guanqiang, Zhang Hua
Tracheal and Bronchial Surgery, Shandong Public Health Clinical Center, Shandong University, Jinan, China.
Department of Oncology, Shandong Provincial Third Hospital, Shandong University, Jinan, China.
Front Mol Biosci. 2025 Aug 1;12:1613539. doi: 10.3389/fmolb.2025.1613539. eCollection 2025.
Tryptophan (Trp) metabolism plays a vital role in tumor development and outcomes. However, Trp in esophageal squamous cell carcinoma (ESCC) remains poorly understood. We aimed to explore the role and mechanism of Trp metabolism in ESCC.
We integrated single-cell RNA (scRNA) sequencing, bulk transcriptome, proteomics, and microbiome data from public databases. Tryptophan-related cell populations and their interactions were explored using the "seurat" R package at the single-cell level. Least absolute shrinkage and selection operator (LASSO) and univariate Cox regression were used to select prognostic TrpGs and construct a risk model. The overall survival, immune infiltration, checkpoint expression, drug sensitivity, and microbiota composition between high- and low-risk groups were evaluated. Independent prognostic factors were identified via multivariate Cox analysis and validated by qPCR analysis, and a nomogram was constructed for survival prediction.
We identified 28 differentially expressed tryptophan-related genes (DE-TrpGs), and fibroblasts emerged as the cell type with the highest TrpG score, although reduced in ESCC. Eighteen DE-TrpGs showed downregulation in tumor fibroblasts at the single-cell level. Fibroblast-epithelial communication involved the LAMININ, HSPG, and AGRN pathways. Five prognostic TrpGs (MAOA, AKR1A1, ALDH9A1, HAAO, and ALDH2) were selected to construct the risk model. The expression of MAOA, AKR1A1, ALDH9A1, HAAO, and ALDH2 was significantly downregulated in ESCC tumor tissues compared to non-tumor tissues. High-risk patients showed poorer overall survival (OS), distinct immune cell infiltration, elevated expression of KIR2DL1, LGALS9, TNFRSF18, and TNFRSF4, increased sensitivity to imatinib and axitinib, resistance to multiple chemotherapeutics, and reduced and abundance. HAAO, ALDH2, and lymph node stage were identified as independent prognostic factors and were used to develop a predictive nomogram.
We identified a Trp metabolism-associated fibroblast population in the ESCC tumor microenvironment (TME) and developed a five-gene TrpG signature for prognostic prediction in ESCC patients.
色氨酸（Trp）代谢在肿瘤发展及预后中起着至关重要的作用。然而，食管鳞状细胞癌（ESCC）中的色氨酸情况仍知之甚少。我们旨在探究色氨酸代谢在ESCC中的作用及机制。
我们整合了来自公共数据库的单细胞RNA（scRNA）测序、批量转录组、蛋白质组学和微生物组数据。使用“seurat”R包在单细胞水平上探索色氨酸相关细胞群体及其相互作用。采用最小绝对收缩和选择算子（LASSO）和单变量Cox回归来选择预后色氨酸基因（TrpGs）并构建风险模型。评估高风险组和低风险组之间的总生存期、免疫浸润、检查点表达、药物敏感性和微生物群组成。通过多变量Cox分析确定独立预后因素，并通过qPCR分析进行验证，构建用于生存预测的列线图。
我们鉴定出28个差异表达的色氨酸相关基因（DE-TrpGs），尽管ESCC中其表达降低，但成纤维细胞是色氨酸基因评分最高的细胞类型。18个DE-TrpGs在单细胞水平的肿瘤成纤维细胞中显示下调。成纤维细胞-上皮细胞通讯涉及层粘连蛋白、硫酸乙酰肝素蛋白聚糖和聚集蛋白聚糖途径。选择5个预后TrpGs（单胺氧化酶A（MAOA）、醛糖还原酶1A1（AKR1A1）、醛脱氢酶9A1（ALDH9A1）、3-羟基犬尿氨酸双加氧酶（HAAO）和醛脱氢酶2（ALDH2））构建风险模型。与非肿瘤组织相比,MAOA、AKR1A1、ALDH9A1、HAAO和ALDH2在ESCC肿瘤组织中的表达显著下调。高风险患者的总生存期（OS）较差，免疫细胞浸润明显不同，杀伤细胞免疫球蛋白样受体2DL1（KIR2DL1）、半乳糖凝集素9（LGALS9）、肿瘤坏死因子受体超家族成员18（TNFRSF18）和肿瘤坏死因子受体超家族成员4（TNFRSF4）表达升高，对伊马替尼和阿西替尼敏感性增加,对多种化疗药物耐药，且粪杆菌属和瘤胃球菌属丰度降低。HAAO、ALDH2和淋巴结分期被确定为独立预后因素，并用于开发预测列线图。
我们在ESCC肿瘤微环境（TME）中鉴定出一个色氨酸代谢相关的成纤维细胞群体，并开发了一种五基因TrpG特征用于ESCC患者的预后预测。
