Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells
Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells
复制标题
单细胞测序揭示了 ARID1A、GPRC5A 和 MLL2 的变异驱动人类膀胱癌干细胞的自我更新。
DOI：
10.1016/j.eururo.2016.06.025
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发表时间：
2017-01-01
期刊：
影响因子：
23.4
通讯作者：
Wu，Song
中科院分区：
文献类型：
--
作者：
Yang，Zhao;Li，Chong;Wu，Song
肿瘤干细胞被认为与肿瘤的许多重要方面有关，如自我更新、肿瘤启动、耐药和转移等。然而，人膀胱癌干细胞(BCSCs)的遗传学基础和起源尚不清楚。在这里，我们对来自三个膀胱癌(BC)标本的59个细胞进行了单细胞测序，包括BCSCs、膀胱癌非干细胞(BCNSCs)、膀胱上皮干细胞(BESCs)和膀胱上皮非干细胞(BENSCs)。具体地说，BCSCs表现出克隆同源性，并通过系统发育分析提示其起源于BESCs或BCNSCs。此外，在BCSCs中发现了21个关键改变基因，其中包括6个在BC中未描述的基因(ETS1、GPRC5A、MKL1、PAWR、PITX2和RGS9BP)。CRISPR/Cas9引入的ARID1A、GPRC5A和MLL2共突变显著增强了BCNSCs的自我更新和致瘤能力。据我们所知，我们的研究首先用单细胞测序的方法概述了人类BCSCs的遗传学基础，并通过进化分析论证了人类BCSCs的双克隆性起源。ARID1A、GPRC5A和MLL2突变使膀胱癌非干细胞具有自我更新的能力。
Cancer stem cells are considered responsible for many important aspects of tumors such as their self-renewal, tumor-initiating, drug-resistance and metastasis. However, the genetic basis and origination of human bladder cancer stem cells (BCSCs) remains unknown. Here, we conducted single-cell sequencing on 59 cells including BCSCs, bladder cancer non-stem cells (BCNSCs), bladder epithelial stem cells (BESCs) and bladder epithelial non-stem cells (BENSCs) from three bladder cancer (BC) specimens. Specifically, BCSCs demonstrate clonal homogeneity and suggest their origin from BESCs or BCNSCs through phylogenetic analysis. Moreover, 21 key altered genes were identified in BCSCs including six genes not previously described in BC (ETS1,GPRC5A,MKL1,PAWR,PITX2andRGS9BP). Co-mutations ofARID1A, GPRC5A and MLL2introduced by CRISPR/Cas9 significantly enhance the capabilities of self-renewal and tumor-initiating of BCNSCs. To our knowledge, our study first provides an overview of the genetic basis of human BCSCs with single-cell sequencing and demonstrates the biclonal origin of human BCSCs via evolution analysis.Patient summaryHuman bladder cancer stem cells show the high level of consistency and may derived from bladder epithelial stem cells or bladder cancer non-stem cells. Mutations ofARID1A, GPRC5AandMLL2grant bladder cancer non-stem cells the capability of self-renewal.