线粒体能量代谢与食管鳞状细胞癌的免疫抑制肿瘤微环境及不良预后相关。
Mitochondrial energy metabolism correlates with an immunosuppressive tumor microenvironment and poor prognosis in esophageal squamous cell carcinoma.
作者信息
Zhang Zewei, Jin Gaowa, Zhao Juan, Deng Shuqin, Chen Feng, Wuyun Gaowa, Zhao Lei, Li Quanfu
机构信息
Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
State Key Laboratory of Oncology in South China, Guangzhou, China.
出版信息
Comput Struct Biotechnol J. 2023 Aug 24;21:4118-4133. doi: 10.1016/j.csbj.2023.08.022. eCollection 2023.
BACKGROUND
Reprogramming of mitochondrial energy metabolism (MEM) is an important hallmark of tumorigenesis and cancer progression. Currently, there are no studies that have examined MEM in the tumor microenvironment (TME) of esophageal squamous cell carcinoma (ESCC), and relevant drug targets have not yet been identified.
METHODS
The ESCC single-cell transcriptome sequencing dataset, GSE145370, was analyzed, using the AUCell R package to screen for MEM-related genes in high-scoring cell populations. Monocle was used to infer cell differentiation and CellChat to analyze intercellular communication networks. Finally, transcription levels of prognostic genes were analyzed using a complementary DNA microarray from 15 patients with ESCC.
RESULTS
A total of 121 MEM-related genes were differentially expressed in seven cell populations in the TME, and four high-scoring cell populations were identified. As a result, the MEM state of T cells is significantly different from that of macrophages and epithelial cells, and signaling communication between T cells and macrophages is the strongest. These findings suggest that immunosuppression is related to metabolic reprogramming. Additionally, marker genes of high-scoring cells and the top10 receptor-ligand pairs may become new targets for rebuilding immune cell metabolism. Furthermore, the 4-MEM gene risk signature had good predictive power for overall survival and drug sensitivity. MAP1LC3A, APOE, APPL1, and NDUFA are novel potential immunotherapeutic targets for remodeling the TME. Finally, teal-time quantitative PCR was used to verify APOE and MAP1LC3A expression.
CONCLUSION
MEM heterogeneity was observed in the immunosupressive TME of ESCC. Prognostic models based on MEM-related genes are helpful for screening early treatment patient groups and realizing personalized treatment. APOE and MAP1LC3A are potential target genes for the development of anti-ESCC drugs based on MEM-related genes.
背景
线粒体能量代谢重编程（MEM）是肿瘤发生和癌症进展的一个重要标志。目前，尚无研究在食管鳞状细胞癌（ESCC）的肿瘤微环境（TME）中检测MEM，相关药物靶点也尚未确定。
方法
分析ESCC单细胞转录组测序数据集GSE145370，使用AUCell R包在高分细胞群体中筛选MEM相关基因。使用Monocle推断细胞分化，使用CellChat分析细胞间通讯网络。最后，使用15例ESCC患者的互补DNA微阵列分析预后基因的转录水平。
结果
共有121个MEM相关基因在TME的7个细胞群体中差异表达，鉴定出4个高分细胞群体。结果显示，T细胞的MEM状态与巨噬细胞和上皮细胞的显著不同，T细胞与巨噬细胞之间的信号通讯最强。这些发现表明免疫抑制与代谢重编程有关。此外，高分细胞的标记基因和前10个受体-配体对可能成为重建免疫细胞代谢的新靶点。此外，4-MEM基因风险特征对总生存期和药物敏感性具有良好的预测能力。MAP1LC3A、APOE、APPL1和NDUFA是重塑TME的新型潜在免疫治疗靶点。最后，使用实时定量PCR验证APOE和MAP1LC3A的表达。
结论
在ESCC的免疫抑制TME中观察到MEM异质性。基于MEM相关基因的预后模型有助于筛选早期治疗患者群体并实现个性化治疗。APOE和MAP1LC3A是基于MEM相关基因开发抗ESCC药物的潜在靶基因。
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