Long Zhilin, Sun Chengfang, Tang Min, Wang Yin, Ma Jiayan, Yu Jichuan, Wei Jingchao, Ma Jianzhu, Wang Bohan, Xie Qi, Wen Jiaming
College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
Cell Discov. 2022 Jul 19;8(1):68. doi: 10.1038/s41421-022-00415-0.
The clear cell renal cell carcinoma (ccRCC) microenvironment consists of many different cell types and structural components that play critical roles in cancer progression and drug resistance, but the cellular architecture and underlying gene regulatory features of ccRCC have not been fully characterized. Here, we applied single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to generate transcriptional and epigenomic landscapes of ccRCC. We identified tumor cell-specific regulatory programs mediated by four key transcription factors (TFs) (HOXC5, VENTX, ISL1, and OTP), and these TFs have prognostic significance in The Cancer Genome Atlas (TCGA) database. Targeting these TFs via short hairpin RNAs (shRNAs) or small molecule inhibitors decreased tumor cell proliferation. We next performed an integrative analysis of chromatin accessibility and gene expression for CD8 T cells and macrophages to reveal the different regulatory elements in their subgroups. Furthermore, we delineated the intercellular communications mediated by ligand-receptor interactions within the tumor microenvironment. Taken together, our multiomics approach further clarifies the cellular heterogeneity of ccRCC and identifies potential therapeutic targets.
透明细胞肾细胞癌（ccRCC）微环境由许多不同的细胞类型和结构成分组成，它们在癌症进展和耐药性中起关键作用，但ccRCC的细胞结构和潜在的基因调控特征尚未完全明确。在此，我们应用单细胞RNA测序（scRNA-seq）和转座酶可及染色质单细胞测序（scATAC-seq）来生成ccRCC的转录组和表观基因组图谱。我们鉴定了由四个关键转录因子（TFs）（HOXC5、VENTX、ISL1和OTP）介导的肿瘤细胞特异性调控程序，并且这些TFs在癌症基因组图谱（TCGA）数据库中具有预后意义。通过短发夹RNA（shRNAs）或小分子抑制剂靶向这些TFs可降低肿瘤细胞增殖。接下来，我们对CD8 T细胞和巨噬细胞的染色质可及性和基因表达进行了综合分析，以揭示其亚组中的不同调控元件。此外，我们描绘了肿瘤微环境中由配体-受体相互作用介导的细胞间通讯。综上所述，我们的多组学方法进一步阐明了ccRCC的细胞异质性并确定了潜在的治疗靶点。
