Zhang Yinmeng, Zhu He, Fan Jiawei, Zhao Jiahui, Xia Yan, Zhang Nan, Xu Hong
Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China.
Front Mol Biosci. 2025 May 15;12:1599141. doi: 10.3389/fmolb.2025.1599141. eCollection 2025.
Colorectal cancer (CRC) remains a major cause of cancer mortality, and dysregulated glutamine metabolism has emerged as a potential therapeutic target. However, the precise role of glutamine in CRC progression and treatment response remains debated.
The authors collected transcriptome and microbiome information, from multiple sources to construct the GLMscore, a prognostic signature in CRC. To comprehensively characterize the biological features of GLMscore groups, the integration of transcriptomic profiling, KEGG pathway enrichment analysis, immune infiltration analysis, tumor immune microenvironment characterization, microbiome analysis, and tissue imaging were applied. Furthermore, CRC patients were stratified into GLMscore high and GLMscore low groups. The robustness of GLMscore was validated in both training and validation cohorts, and the predictive value for immunotherapy response was assessed. Finally, single-cell RNA sequencing (scRNA-seq) analysis was conducted to delineate the differences between GLMscore high and GLMscore low groups.
High GLMscore was associated with elevated expression of pathways related to tumorigenesis, epithelial-mesenchymal transition (EMT), and angiogenesis. Furthermore, high GLMscore patients exhibited an immunosuppressive TME characterized by increased infiltration of M0 and M2 macrophages, reduced overall immune infiltration (supported by ESTIMATE and TIDE scores), and increased expression of immune exclusion and suppression pathways. Analysis of pathological whole-slide images (WSIs) revealed a lack of intratumoral tertiary lymphoid structures (TLSs) in high GLMscore patients. The GLMscore also predicted resistance to common chemotherapeutic agents (using GDSC data) and, importantly, predicted poor response to immunotherapy in the IMvigor210 cohort. Analysis of 16S rRNA gene sequencing data revealed an enrichment of potentially oncogenic microbiota, including Hungatella and Selenomonas, in high GLMscore group. Single-cell analysis further confirmed the immunosuppressive TME and identified increased cell-cell communication between inflammatory macrophages and tumor cells in high GLMscore group.
The authors innovatively constructed GLMscore, a robust scoring system in quantifying CRC patients, exploring the distinct biological features, tumor immune microenvironment and microbiome ecology, exhibiting high validity in predicting survival prognosis and clinical treatment efficacy.
结直肠癌（CRC）仍是癌症死亡的主要原因，谷氨酰胺代谢失调已成为一个潜在的治疗靶点。然而，谷氨酰胺在CRC进展和治疗反应中的精确作用仍存在争议。
作者从多个来源收集转录组和微生物组信息，构建了GLMscore，这是一种CRC的预后特征。为了全面表征GLMscore组的生物学特征，应用了转录组分析、KEGG通路富集分析、免疫浸润分析、肿瘤免疫微环境表征、微生物组分析和组织成像的整合。此外，将CRC患者分为GLMscore高分组和GLMscore低分组。在训练队列和验证队列中验证了GLMscore的稳健性，并评估了其对免疫治疗反应的预测价值。最后，进行单细胞RNA测序（scRNA-seq）分析以描绘GLMscore高分组和GLMscore低分组之间的差异。
高GLMscore与肿瘤发生、上皮-间质转化（EMT）和血管生成相关通路的表达升高有关。此外，高GLMscore患者表现出免疫抑制性肿瘤微环境，其特征是M0和M2巨噬细胞浸润增加、总体免疫浸润减少（由ESTIMATE和TIDE评分支持）以及免疫排斥和抑制通路的表达增加。对病理全切片图像（WSIs）的分析显示，高GLMscore患者缺乏肿瘤内三级淋巴结构（TLSs）。GLMscore还预测了对常用化疗药物的耐药性（使用GDSC数据），重要的是，预测了IMvigor210队列中对免疫治疗的不良反应。对16S rRNA基因测序数据的分析显示，高GLMscore组中潜在致癌微生物群富集，包括Hungatella和Selenomonas。单细胞分析进一步证实了免疫抑制性肿瘤微环境，并确定了高GLMscore组中炎症巨噬细胞与肿瘤细胞之间细胞间通讯增加。
作者创新性地构建了GLMscore，这是一种强大的评分系统，用于量化CRC患者，探索独特的生物学特征、肿瘤免疫微环境和微生物组生态，在预测生存预后和临床治疗疗效方面具有很高的有效性。
