Revealing the transcriptional heterogeneity of organ‐specific metastasis in human gastric cancer using single‐cell RNA Sequencing

作者：Haiping Jiang, Dingyi Yu, Penghui Yang, Rongfang Guo, Mei Kong, Yuan Gao, Xiongfei Yu, Xiaoyan Lu, Xiaohui Fan · 发表于：Clinical and Translational Medicine · 年份：2022 · DOI：10.1002/ctm2.730 · 被引用次数：258 · 研究领域：Single-cell and spatial transcriptomics、Ferroptosis and cancer prognosis、Cancer Genomics and Diagnostics

Abstract Background Deciphering intra‐ and inter‐tumoural heterogeneity is essential for understanding the biology of gastric cancer (GC) and its metastasis and identifying effective therapeutic targets. However, the characteristics of different organ‐tropism metastases of GC are largely unknown. Methods Ten fresh human tissue samples from six patients, including primary tumour and adjacent non‐tumoural samples and six metastases from different organs or tissues (liver, peritoneum, ovary, lymph node) were evaluated using single‐cell RNA sequencing. Validation experiments were performed using histological assays and bulk transcriptomic datasets. Results Malignant epithelial subclusters associated with invasion features, intraperitoneal metastasis propensity, epithelial–mesenchymal transition‐induced tumour stem cell phenotypes, or dormancy‐like characteristics were discovered. High expression of the first three subcluster‐associated genes displayed worse overall survival than those with low expression in a GC cohort containing 407 samples. Immune and stromal cells exhibited cellular heterogeneity and created a pro‐tumoural and immunosuppressive microenvironment. Furthermore, a 20‐gene signature of lymph node‐derived exhausted CD8 + T cells was acquired to forecast lymph node metastasis and validated in GC cohorts. Additionally, although anti‐NKG2A (KLRC1) antibody have not been used to treat GC patients even in clinical trials, we uncovered not only malignant tumour cells but ...