Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq.
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq.
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DOI：
10.1126/science.aad0501
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发表时间：
2016-04-08
期刊：
影响因子：
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通讯作者：
Garraway LA
中科院分区：
文献类型：
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作者：
Tirosh I;Izar B;Prakadan SM;Wadsworth MH 2nd;Treacy D;Trombetta JJ;Rotem A;Rodman C;Lian C;Murphy G;Fallahi-Sichani M;Dutton-Regester K;Lin JR;Cohen O;Shah P;Lu D;Genshaft AS;Hughes TK;Ziegler CG;Kazer SW;Gaillard A;Kolb KE;Villani AC;Johannessen CM;Andreev AY;Van Allen EM;Bertagnolli M;Sorger PK;Sullivan RJ;Flaherty KT;Frederick DT;Jané-Valbuena J;Yoon CH;Rozenblatt-Rosen O;Shalek AK;Regev A;Garraway LA
为了探索黑色素瘤肿瘤不同的基因和表型状态，我们对19名患者分离的4645个单细胞应用了单细胞RNA-SEQ，分析了恶性细胞、免疫细胞、间质细胞和内皮细胞。同一肿瘤内的恶性细胞表现出与细胞周期、空间背景和耐药程序相关的转录异质性。具体地说，所有肿瘤都含有来自两种不同转录细胞状态的恶性细胞，因此“MITF-High”肿瘤也包含“Axl-High”肿瘤细胞。单细胞分析提出了不同的肿瘤微环境模式，包括细胞与细胞之间的相互作用。对肿瘤浸润性T细胞的分析揭示了耗竭程序，它们与T细胞激活和克隆性增殖的联系，以及它们在患者中的变异性。总体而言，我们开始解开肿瘤的细胞生态系统，以及单细胞基因组学如何提供具有靶向和免疫治疗意义的见解。
To explore the distinct genotypic and phenotypic states of melanoma tumors we applied single-cell RNA-seq to 4,645 single cells isolated from 19 patients, profiling malignant, immune, stromal and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that “MITF-high” tumors also contained “AXL-high” tumor cells. Single-cell analyses suggested distinct tumor micro-environmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and to clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single cell genomics offers insights with implications for both targeted and immune therapies.