Single-cell RNA-seq reveals dynamic change in tumor microenvironment during pancreatic ductal adenocarcinoma malignant progression.
Single-cell RNA-seq reveals dynamic change in tumor microenvironment during pancreatic ductal adenocarcinoma malignant progression.
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单细胞RNA-seq揭示胰腺导管腺癌恶性进展过程中肿瘤微环境的动态变化
DOI：
10.1016/j.ebiom.2021.103315
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发表时间：
2021-04
期刊：
影响因子：
11.1
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Chen K;Wang Q;Li M;Guo H;Liu W;Wang F;Tian X;Yang Y
胰腺导管腺癌（PDAC）是所有胃肠道肿瘤中最具侵袭性的。PDAC复杂的肿瘤内异质性和特殊的肿瘤微环境给有效的治疗策略带来了巨大的挑战。我们的目的是利用单细胞RNA测序描绘PDAC恶性进展过程中肿瘤微环境成分的动态变化。共11个样品（4个PDAC I，4个PDAC II，3个PDAC III）用于构建表达基质。在鉴定不同的细胞簇后，对每个簇进行亚簇分析。通过加权基因共表达网络分析、RNA原位杂交和免疫荧光等方法对新的癌相关成纤维细胞（CAFs）亚群进行验证。我们发现导管细胞不是主要成分，而肿瘤浸润的免疫细胞和胰腺星状细胞在肿瘤发展过程中逐渐积累。我们定义了几个新的Treg和耗尽的T细胞标记基因，包括DUSP 4，FANK 1和LAIR 2。TCGA数据集分析显示，DUSP 4高表达的患者预后明显较差。此外，我们还发现了一个新的CAFs亚群（complement-secreting CAFs，csCAFs），该亚群特异性表达补体系统成分，并通过加权基因共表达网络分析构建了csCAFs相关模块。csCAFs仅在早期PDAC中位于恶性导管细胞附近的组织间质中。我们系统地研究了PDAC的异质性，并将csCAFs鉴定为PDAC特有的一个新的CAFs亚群，这可能对理解肿瘤内部的串扰有价值。本研究得到了国家自然科学基金（NO.81572339，81672353，81871954）和北京大学第一医院青年临床研究项目（2018 CR28）的资助。
Pancreatic ductal adenocarcinoma (PDAC) is most aggressive among all gastrointestinal tumors. The complex intra-tumor heterogeneity and special tumor microenvironment in PDAC bring great challenges for developing effective treatment strategies. We aimed to delineate dynamic changes of tumor microenvironment components during PDAC malignant progression utilizing single-cell RNA sequencing. A total of 11 samples (4 PDAC I, 4 PDAC II, 3 PDAC III) were used to construct expression matrix. After identifying distinct cell clusters, subcluster analysis for each cluster was performed. New cancer associated fibroblasts (CAFs) subset was validated by weighted gene co-expression network analysis, RNA in situ hybridization and immunofluorescence. We found that ductal cells were not dominant component while tumor infiltrating immune cells and pancreatic stellate cells gradually accumulated during tumor development. We defined several new Treg and exhausted T cell signature genes, including DUSP4, FANK1 and LAIR2. The analysis of TCGA datasets showed that patients with high expression of DUSP4 had significantly worse prognosis. In addition, we identified a new CAFs subset (complement-secreting CAFs, csCAFs), which specifically expresses complement system components, and constructed csCAFs-related module by weighted gene co-expression network analysis. The csCAFs were located in the tissue stroma adjacent to malignant ductal cells only in early PDAC. We systematically explored PDAC heterogeneity and identified csCAFs as a new CAFs subset special to PDAC, which may be valuable for understanding the crosstalk inside tumor. This study was supported by The Natural Science Foundation of China (NO.81572339, 81672353, 81871954) and the Youth Clinical Research Project of Peking University First Hospital (2018CR28).
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影响因子：
3
作者：
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通讯作者：
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影响因子：
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作者：
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