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. 2021 Nov 15;27(22):6265-6278.
doi: 10.1158/1078-0432.CCR-20-4796. Epub 2021 Sep 15.

Single-Cell Analyses Reveal Mechanisms of Cancer Stem Cell Maintenance and Epithelial-Mesenchymal Transition in Recurrent Bladder Cancer

Huanjun Wang #  1 , Yan Mei #  2 , Cheng Luo #  3 , Qun Huang #  4 , Zifeng Wang #  5 , Guan-Ming Lu  6 , Lili Qin  7 , Zhun Sun  7 , Chao-Wen Huang  8 , Zhi-Wen Yang  9 , Junxing Chen  3 , Weiguo Yin  10 , Chao-Nan Qian  5 , Jianming Zeng  11 , Lingwu Chen  12 , Qibin Leng  13   10 , Yan Guo  14 , Guangshuai Jia  13   10
Affiliations

Single-Cell Analyses Reveal Mechanisms of Cancer Stem Cell Maintenance and Epithelial-Mesenchymal Transition in Recurrent Bladder Cancer

Huanjun Wang et al. Clin Cancer Res. .

Abstract

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.

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