Revealing the transcriptional heterogeneity of organ-specific metastasis in human gastric cancer using single-cell RNA Sequencing.
Revealing the transcriptional heterogeneity of organ-specific metastasis in human gastric cancer using single-cell RNA Sequencing.
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使用单细胞 RNA 测序揭示人胃癌器官特异性转移的转录异质性
DOI：
10.1002/ctm2.730
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发表时间：
2022-03
影响因子：
10.6
通讯作者：
Fan X
中科院分区：
文献类型：
--
作者：
Jiang H;Yu D;Yang P;Guo R;Kong M;Gao Y;Yu X;Lu X;Fan X
解读肿瘤内和肿瘤间的异质性对于理解胃癌（GC）及其转移的生物学和确定有效的治疗靶点至关重要。然而，GC的不同器官嗜性转移的特征在很大程度上是未知的。使用单细胞RNA测序评价了来自6名患者的10份新鲜人体组织样本，包括原发性肿瘤和相邻非肿瘤样本以及来自不同器官或组织（肝脏、腹膜、卵巢、淋巴结）的6个转移灶。使用组织学测定和批量转录组数据集进行验证实验。发现了与侵袭特征、腹膜内转移倾向、上皮-间质转化诱导的肿瘤干细胞表型或休眠样特征相关的恶性上皮亚群。在包含407个样本的GC队列中，前三个亚簇相关基因的高表达显示出比低表达的基因更差的总生存期。免疫和基质细胞表现出细胞异质性，并创造了促肿瘤和免疫抑制微环境。此外，获得了淋巴结来源的耗尽的CD 8 + T细胞的20个基因签名，以预测淋巴结转移，并在GC队列中进行了验证。此外，尽管抗NKG 2A（KLRC 1）抗体尚未用于治疗GC患者，甚至在临床试验中，我们不仅发现了恶性肿瘤细胞，还发现了一种内皮亚群，粘膜相关的不变T细胞，T细胞样B细胞，浆细胞样树突状细胞，巨噬细胞，单核细胞，和中性粒细胞可能有助于HLA-E-KLRC 1/KLRC 2与细胞毒性/耗竭的CD 8 + T细胞和/或自然杀伤（NK）细胞的相互作用，提示GC的新的临床治疗机会。此外，我们的研究结果表明，CD 8 + T细胞中的PD-1表达可能预测GC对PD-1阻断治疗的临床反应。这项研究提供了对GC原发性肿瘤和器官特异性转移的异质性微环境的见解，并为精确诊断和治疗提供支持。1)在GC中进行器官特异性转移（肝、腹膜、卵巢、淋巴结）的单细胞RNA测序。2)单细胞分析确定了GC中四种恶性上皮亚型的表型和功能。3)淋巴结来源的耗尽的CD 8 + T细胞的20个基因签名可能预测淋巴结转移，靶向HLA-E-KLRC 1/KLRC 2信号转导为GC的临床治疗提供了新的机会。
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. 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. 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 one endothelial subcluster, mucosal‐associated invariant T cells, T cell‐like B cells, plasmacytoid dendritic cells, macrophages, monocytes, and neutrophils may contribute to HLA‐E‐KLRC1/KLRC2 interaction with cytotoxic/exhausted CD8+ T cells and/or natural killer (NK) cells, suggesting novel clinical therapeutic opportunities in GC. Additionally, our findings suggested that PD‐1 expression in CD8+ T cells might predict clinical responses to PD‐1 blockade therapy in GC. This study provided insights into heterogeneous microenvironment of GC primary tumours and organ‐specific metastases and provide support for precise diagnosis and treatment. 1) Single‐cell RNA‐seq of organ‐specific metastasis (liver, peritoneum, ovary, lymph node) in GC was conducted. 2) Single‐cell analysis determined phenotypes and functions of four malignant epithelial subtypes in GC. 3) A 20‐gene signature of lymph node‐derived exhausted CD8+ T cells might forecast lymph node metastasis, and targeting HLA‐E‐KLRC1/KLRC2 signaling severs as a novel clinical therapeutic opportunity for GC.
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影响因子：
24.5
作者：
Arnold, Melina;Ferlay, Jacques;Soerjomataram, Isabelle
通讯作者：
Soerjomataram, Isabelle
单细胞 RNA 测序强调了炎性癌症相关成纤维细胞在膀胱尿路上皮癌中的作用。
影响因子：
16.6
作者：
Chen Z;Zhou L;Liu L;Hou Y;Xiong M;Yang Y;Hu J;Chen K
通讯作者：
Chen K
子宫内膜样腺癌淋巴管间隙受累及淋巴结转移过程中免疫微环境及信号通路的重建
影响因子：
4.7
作者：
Cheng Y;Zhang X;Wang Z;Wang J
通讯作者：
Wang J
DOI：
10.1073/pnas.1815345116
发表时间：
2019-01-02
影响因子：
11.1
作者：
Bocci, Federico;Gearhart-Serna, Larisa;Jolly, Mohit Kumar
通讯作者：
Jolly, Mohit Kumar
影响因子：
64.5
作者：
André P;Denis C;Soulas C;Bourbon-Caillet C;Lopez J;Arnoux T;Bléry M;Bonnafous C;Gauthier L;Morel A;Rossi B;Remark R;Breso V;Bonnet E;Habif G;Guia S;Lalanne AI;Hoffmann C;Lantz O;Fayette J;Boyer-Chammard A;Zerbib R;Dodion P;Ghadially H;Jure-Kunkel M;Morel Y;Herbst R;Narni-Mancinelli E;Cohen RB;Vivier E
通讯作者：
Vivier E