Single-cell RNA sequencing reveals tissue architecture during human high-grade serous ovarian cancer progression

As the most fatal type of gynecological cancers, high-grade serous ovarian cancer (HGSOC) exhibits heterogeneity that obstacles therapeutics. Up to date, the pathogenesis of HGSOC remains poorly understood. Here, we performed the deep single-cell RNA sequencing (scRNA-seq) using 59,324 cells isolated from seven treatment-naïve HGSOC patients at early or late tumor stages and five age-matched non-malignant ovarian samples. Our sequencing data showed a highly complex ecosystem of tumor, immune and stromal cells based on their marker genes and functional properties. We showed that normal ovary-specific fibroblasts were carried with the properties of mesenchymal stem cells (MSCs), which could be reprogrammed to cancer-associated fibroblasts. During tumor progression, matrix CAFs (mCAFs) could induce the EMT properties of the tumor cells. Furthermore, the analysis of the early stage tumors illuminated enrichments of IDO-expressing macrophages, CD8+ TRM cells, and the activated CD8+ TEX cells (TRM-CXCL13), whereas those tumors at the late stages loss these features and expressed signatures related to epithelial-to-mesenchymal transition (EMT) program. Also, we characterized a specific chemokine-receptor communication in HGSOC tumor microenvironment, which may contribute to shape the HGSOC features. Our compendia of scRNA-seq results provide valuable insights for understanding the landscape of HGSOC ecosystem, which will be helpful in advancing HGSOC cancer diagnosis and therapy and enabling personalized approaches to the treatment. Overall design: landscape of HGSOC ecosystem

作为最致命的妇科癌症类型之一，高级别浆液性卵巢癌（high-grade serous ovarian cancer, HGSOC）存在显著异质性，这对临床治疗构成阻碍。迄今为止，学界对HGSOC的发病机制仍缺乏深入认知。本研究针对7名初治HGSOC患者（涵盖肿瘤早晚期）及5名年龄匹配的非恶性卵巢组织样本，分离得到59324个细胞并开展了深度单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）。测序数据显示，基于标记基因与功能特性，肿瘤、免疫及基质细胞共同构成了高度复杂的生态系统。研究发现，正常卵巢特异性成纤维细胞具备间充质干细胞（mesenchymal stem cells, MSCs）的特性，且可被重编程为癌相关成纤维细胞（cancer-associated fibroblasts, CAFs）。在肿瘤进展过程中，基质癌相关成纤维细胞（matrix CAFs, mCAFs）可诱导肿瘤细胞产生上皮间质转化（epithelial-to-mesenchymal transition, EMT）表型。进一步分析早期肿瘤样本发现，其富集表达IDO的巨噬细胞、CD8+组织驻留记忆T细胞（CD8+ TRM cells）以及活化的CD8+耗竭T细胞（CD8+ TEX cells, TRM-CXCL13）；而晚期肿瘤则缺失此类特征，转而呈现上皮间质转化程序相关的分子特征。此外，本研究还解析了HGSOC肿瘤微环境中一类特异性的趋化因子-受体互作网络，该网络或参与塑造HGSOC的肿瘤生物学特征。本研究的单细胞RNA测序数据集为解析HGSOC生态系统的全貌提供了宝贵见解，有助于推动HGSOC的诊断与治疗研究，并为个性化治疗方案的开发提供支撑。总体研究设计：HGSOC生态系统全景图谱