Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Bioinformatics and Computational Biology Graduate Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Mol Cell. 2021 Dec 2;81(23):4924-4941.e10. doi: 10.1016/j.molcel.2021.10.013. Epub 2021 Nov 4.
Deconvolution of regulatory mechanisms that drive transcriptional programs in cancer cells is key to understanding tumor biology. Herein, we present matched transcriptome (scRNA-seq) and chromatin accessibility (scATAC-seq) profiles at single-cell resolution from human ovarian and endometrial tumors processed immediately following surgical resection. This dataset reveals the complex cellular heterogeneity of these tumors and enabled us to quantitatively link variation in chromatin accessibility to gene expression. We show that malignant cells acquire previously unannotated regulatory elements to drive hallmark cancer pathways. Moreover, malignant cells from within the same patients show substantial variation in chromatin accessibility linked to transcriptional output, highlighting the importance of intratumoral heterogeneity. Finally, we infer the malignant cell type-specific activity of transcription factors. By defining the regulatory logic of cancer cells, this work reveals an important reliance on oncogenic regulatory elements and highlights the ability of matched scRNA-seq/scATAC-seq to uncover clinically relevant mechanisms of tumorigenesis in gynecologic cancers.
解析驱动癌细胞中转录程序的调控机制是理解肿瘤生物学的关键。在此，我们呈现了在人卵巢和子宫内膜肿瘤中，从即刻手术切除后处理的单细胞分辨率获得的匹配转录组（scRNA-seq）和染色质可及性（scATAC-seq）图谱。该数据集揭示了这些肿瘤的复杂细胞异质性，并使我们能够定量地将染色质可及性的变化与基因表达联系起来。我们表明，恶性细胞获得了以前未注释的调控元件，以驱动标志性的癌症途径。此外，来自同一患者的恶性细胞显示出与转录输出相关的染色质可及性的显著差异，突出了肿瘤内异质性的重要性。最后，我们推断了转录因子的恶性细胞类型特异性活性。通过定义癌细胞的调控逻辑，这项工作揭示了对致癌调控元件的重要依赖，并强调了匹配的 scRNA-seq/scATAC-seq 揭示妇科癌症中与肿瘤发生相关的临床相关机制的能力。
