Single-cell analysis reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of ovarian cancer.
Single-cell analysis reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of ovarian cancer.
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单细胞分析揭示了卵巢癌微环境中的间质动力学和肿瘤特异性特征。
DOI：
10.1038/s42003-023-05733-x
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发表时间：
2024-01-05
影响因子：
5.9
通讯作者：
Osmanbeyoglu, Hatice Ulku
中科院分区：
文献类型：
--
作者：
Zhang, Linan;Cascio, Sandra;Mellors, John W.;Buckanovich, Ronald J.;Osmanbeyoglu, Hatice Ulku
高级别浆液性卵巢癌（HGSOC）是一种异质性疾病，高间质/结缔组织增生肿瘤微环境（TME）与不良预后相关。基质细胞亚型，包括成纤维细胞、肌成纤维细胞和癌症相关间充质干细胞，与肿瘤浸润免疫细胞建立复杂的旁分泌信号通路网络，驱动效应细胞肿瘤免疫排斥并抑制抗肿瘤免疫反应。在这项工作中，我们整合了来自公共和内部数据集（n = 20）的HGSOC TME的单细胞转录组学，并根据基质细胞含量高低对肿瘤进行分层。虽然我们的队列规模很小，但我们的分析表明，在高基质肿瘤和低基质肿瘤中，免疫细胞和非免疫细胞的转录组学景观截然不同。高间质肿瘤的某些T细胞、自然杀伤细胞（NK）和巨噬细胞的比例较低，并且CXCL12在上皮癌细胞和癌症相关间充质干细胞（CA-MSCs）中的表达增加。细胞间通讯分析表明，上皮癌细胞和CA-MSCs分泌与CXCR4受体相互作用的CXCL12，该受体在NK细胞和CD8+ T细胞上过表达。双免疫组化染色显示肿瘤浸润的CD8 T细胞定位于CXCL12+肿瘤区域附近。此外，CXCL12和/或CXCR4抗体证实了CXCL12-CXCR4在高间质肿瘤中的免疫抑制作用。一项卵巢癌的单细胞转录组学综合研究显示，高基质瘤和低基质瘤在肿瘤免疫细胞浸润谱（热与冷）中具有不同的类别。高基质细胞水平与免疫抑制表型相关。
High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a highstromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. In this work, we integrate single-cell transcriptomics of the HGSOC TME from public and in-house datasets (n = 20) and stratify tumors based upon high vs. low stromal cell content. Although our cohort size is small, our analyses suggest a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors have a lower fraction of certain T cells, natural killer (NK) cells, and macrophages, and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicate that epithelial cancer cells and CA-MSCs secrete CXCL12 that interacte with the CXCR4 receptor, which is overexpressed on NK and CD8+ T cells. Dual IHC staining show that tumor infiltrating CD8 T cells localize in proximity of CXCL12+ tumor area. Moreover, CXCL12 and/or CXCR4 antibodies confirm the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors. An integrative single-cell transcriptomics study of ovarian cancer shows high and low stromal tumors have distinct classes in tumor-immune cell infiltration spectrum (hot vs cold). High stromal cell levels correlate with an immunosuppressive phenotype.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
3.7
作者：
McCann CK;Growdon WB;Kulkarni-Datar K;Curley MD;Friel AM;Proctor JL;Sheikh H;Deyneko I;Ferguson JA;Vathipadiekal V;Birrer MJ;Borger DR;Mohapatra G;Zukerberg LR;Foster R;Macdougall JR;Rueda BR
通讯作者：
Rueda BR
影响因子：
50.3
作者：
Hornburg, Milena;Desbois, Melanie;Wang, Yulei
通讯作者：
Wang, Yulei
DOI：
10.1073/pnas.1320318110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
通讯作者：
Fearon, Douglas T.
影响因子：
4.4
作者：
Bellamri, Nessrine;Viel, Roselyne;Vernhet, Laurent
通讯作者：
Vernhet, Laurent