Single-Cell Analyses Reveal Mechanisms of Cancer Stem Cell Maintenance and Epithelial-Mesenchymal Transition in Recurrent Bladder Cancer
Single-Cell Analyses Reveal Mechanisms of Cancer Stem Cell Maintenance and Epithelial-Mesenchymal Transition in Recurrent Bladder Cancer
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单细胞分析揭示了复发性膀胱癌中癌症干细胞维持和上皮间质转化的机制。
DOI：
10.1158/1078-0432.ccr-20-4796
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发表时间：
2021-11-01
影响因子：
11.5
通讯作者：
Jia, Guangshuai
中科院分区：
文献类型：
--
作者：
Wang, Huanjun;Mei, Yan;Jia, Guangshuai
目的：膀胱癌的治疗仍然是由于耐药性和高复发率而导致的主要临床挑战。经过肿瘤内的异质性可以揭示膀胱癌复发的分子机制。实验性设计：在这里，我们使用测序（ATAC-SEQ）对13例患者的肿瘤进行了terment蛋白（ATAC-SEQ）进行单细胞RNA测序和测定，并对13例复发风险，更复发的癌症进行了癌症，癌症的癌症，癌症癌症的癌症。由54,971个单细胞组成，并确定了不同的细胞亚群。我们发现，在膀胱癌复发期间，癌症干细胞亚群富集，EZH2表达升高。我们进一步定义了一种亚群特异性的分子机制，在该机制中，EZH2维持了H3K27me3介导的NCAM1基因的抑制，从而灭活了细胞的侵入性和Stemness转录程序。此外，利用了这个大型的单细胞数据集，我们阐明了临床样品中上皮 - 间质转变（EMT）的光谱，并揭示了与膀胱癌亚型相关的不同EMT特征。我们确定TCF7通过具有高通量测序（SCATAC-SEQ）分析的单细胞ATAC促进EMT。此外，我们构建了针对复发性膀胱癌的特定的调节网络。结论：我们的研究和分析方法为进一步研究膀胱癌研究领域的癌症干细胞和EMT提供了丰富的资源。
Purpose: Bladder cancer treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of bladder cancer recurrence.Experimental Design: Here, we performed single-cell RNA sequencing and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on tumors from 13 patients with low recurrence risk, high recurrence risk, and recurrent bladder cancer.Results: Our study generated a comprehensive cancer-cell atlas consisting of 54,971 single cells and identified distinct cell subpopulations. We found that the cancer stem-cell subpopulation is enriched during bladder cancer recurrence with elevated expression of EZH2. We further defined a subpopulation-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the NCAM1 gene, thereby inactivating the cell invasive and stemness transcriptional program. Furthermore, taking advantage of this large single-cell dataset, we elucidated the spectrum of epithelial-mesenchymal transition (EMT) in clinical samples and revealed distinct EMT features associated with bladder cancer subtypes. We identified that TCF7 promotes EMT in corroboration with single-cell ATAC with high-throughput sequencing (scATAC-seq) analysis. Additionally, we constructed regulatory networks specific to recurrent bladder cancer.Conclusions: Our study and analytic approaches herein provide a rich resource for the further study of cancer stem cells and EMT in the bladder cancer research field.