Wang Zixun, Yang Linlin, Su Xiaoye, Wu Xiaomei, Su Rongjia
Nanshan School, Guangzhou Medical University, Guangzhou, China.
Department of Gynecological Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Gene Med. 2023 Oct;25(10):e3504. doi: 10.1002/jgm.3504. Epub 2023 Apr 26.
Tumor resistance is one of the main reasons leading to the failure of ovarian cancer treatment. Overcoming platinum resistance remains the greatest challenge in the management of high-grade serous ovarian carcinoma (HGSC).
Small conditional RNA-sequencing is a powerful method for exploring the complexity of the cellular components and their interactions in the tumor microenvironment. We profiled the transcriptomes of 35,042 cells from two platinum-sensitive and three platinum resistance HGSC clinical cases downloaded from Gene Expression Omnibus (GSE154600) and annotated tumor cells as platinum-resistant or sensitive based on the clinical trait. The study systematically investigated the inter-tumoral (using differential expression analysis, CellChat, and SCENIC) and intra-tumoral heterogeneity (using enrichment analysis such as gene set enrichment analysis, as well as gene set variation analysis, weighted gene correlation network analysis, and Pseudo-time analysis) of HGSC.
A cellular map of HGSC generated by profiling 30,780 cells was revisualized using Uniform Manifold Approximation and Projection. The inter-tumoral heterogeneity was demonstrated with intercellular ligand-receptor interactions of major cell types and regulons networks. FN1, SPP1, and COLLAGEN play important roles in the cross-talk between tumor cells and the tumor microenvironment. HOXA7, HOXA9_extended, TBL1XR1_extended, KLF5, SOX17, and CTCFL regulons consistent with the distribution of platinum-resistant HGSC cells were the high activity regions. The intra-tumoral heterogeneity of HGSC was presented with corresponding functional pathway characteristics, tumor stemness features, and the cellular lineage transition from platinum-sensitive to resistant condition. Epithelial-mesenchymal transition played an important role in platinum resistance, whereas oxidative phosphorylation was the opposite. There was a small subset of cells in platinum-sensitive samples that had transcriptomic characteristics similar to platinum-resistant cells, suggesting that the progression of platinum resistance in ovarian cancer is inevitable.
The present study describes a view of HGSC at single-cell resolution that reveals the characteristics of the HGSC heterogeneity and provides a useful framework for future investigation of platinum-resistant.
肿瘤耐药是导致卵巢癌治疗失败的主要原因之一。克服铂耐药仍然是高级别浆液性卵巢癌（HGSC）治疗中最大的挑战。
小条件RNA测序是一种强大的方法，用于探索肿瘤微环境中细胞成分的复杂性及其相互作用。我们对从基因表达综合数据库（GSE154600）下载的2例铂敏感和3例铂耐药HGSC临床病例中的35042个细胞的转录组进行了分析，并根据临床特征将肿瘤细胞注释为铂耐药或敏感。该研究系统地研究了HGSC的肿瘤间异质性（使用差异表达分析、CellChat和SCENIC）和肿瘤内异质性（使用基因集富集分析等富集分析，以及基因集变异分析、加权基因共表达网络分析和伪时间分析）。
通过对30780个细胞进行分析生成的HGSC细胞图谱使用均匀流形近似和投影进行了重新可视化。肿瘤间异质性通过主要细胞类型的细胞间配体-受体相互作用和调控子网络得以体现。FN1、SPP1和胶原蛋白在肿瘤细胞与肿瘤微环境的相互作用中起重要作用。与铂耐药HGSC细胞分布一致的HOXA7、HOXA9_extended、TBL1XR1_extended、KLF5、SOX17和CTCFL调控子是高活性区域。HGSC的肿瘤内异质性表现为相应的功能通路特征、肿瘤干性特征以及从铂敏感状态到耐药状态的细胞谱系转变。上皮-间质转化在铂耐药中起重要作用，而氧化磷酸化则相反。在铂敏感样本中有一小部分细胞具有与铂耐药细胞相似的转录组特征，这表明卵巢癌中铂耐药的进展是不可避免的。
本研究以单细胞分辨率描述了HGSC的情况，揭示了HGSC异质性的特征，并为未来铂耐药研究提供了有用的框架。
