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Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma

查看全文 作　　者：Junya [1]Peng;Bao-Fa [2,3,4]Sun;Chuan-Yuan [2,3]Chen;Jia-Yi [2,3]Zhou;Yu-Sheng [2,3]Chen;Hao [5]Chen;Lulu [1]Liu;Dan [1]Huang;Jialin [5]Jiang;Guan-Shen [2,3]Cui;Ying [2,3,4]Yang;Wenze [6]Wang;Dan [1,7]Guo;Menghua [5]Dai;Junchao [5]Guo;Taiping [5]Zhang;Quan [5]Liao;Yi [8]Liu;Yong-Liang [2,3,4]Zhao;Da-Li [2,3,4]Han;Yupei [5,8]Zhao;Yun-Gui [2,3,4]Yang;Wenming [5]Wu 高影响力作者 机构地区：[1]Department of Medical Research Center,Peking Union Medical College Hospital,Chinese Academy of Medical Science & Peking Union Medical College,100730 Beijing,China;[2]CAS Key Laboratory of Genomic and Precision Medicine,Collaborative Innovation Center of Genetics and Development,College of Future Technology,Beijing Institute of Genomics,Chinese Academy of Sciences,100101 Beijing,China;[3]University of Chinese Academy of Sciences,100049 Beijing,China;[4]Institute of Stem Cell and Regeneration,Chinese Academy of Sciences,100101 Beijing,China;[5]Department of General Surgery,Peking Union Medical College Hospital,Chinese Academy of Medical Science & Peking Union Medical College,100730 Beijing,China;[6]Department of Pathology,Peking Union Medical College Hospital,Chinese Academy of Medical Science & Peking Union Medical College,100730 Beijing,China;[7]Clinical Biobank,Peking Union Medical College Hospital,Chinese Academy of Medical Science & Peking Union Medical College,100730 Beijing,China;[8]Tsinghua University-Peking University Joint Center for Life Sciences,School of Medicine,Tsinghua University,100084 Beijing,China高影响力机构 出　　处：《Cell Research》索引2019年第29卷第9期,共14页高影响力期刊 基　　金：We thank Dongjing Li for the project coordination.We are grateful to Lin Cong, Ge Chen, Xianlin Han, Ya Hu, Ziwen Liu, Xiequn Xu, Xiaodong He for performing pancreatic surgeries, and to Zhixuan Xuan,Dingyan Cao for collecting pancreatic specimens.We thank the department of Pathology, the center lab of PUMCH, and to Junyi Pang and Ying Wang and Mengqing Sun for assistance with IHC staining, frozen section and schematic drawing. We thank Jin Yang and Qiuhui Qi for assistance with the single-cell RNA-seq.This work was supported by the Key Research Program of the Chinese Academy of Sciences (KJZD-SW-L01), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16000000 to Y.-G.Y.);the Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (CAMS-I2M) 2017-I2M-1-001,the National Nature Science Foundation of China (No.31625016 to Y.-G.Y.,No.81672443 to Y.PZ,No.81773292 to W.M.W., No.31701171 to J.Y.P., No.91853132 to D.-L.H.);Youth Innovation Promotion Association, CAS(2016097 to B.-F.S.);CAS Hundred Talent Program (to D.-LH.),National Key Research and Development Program of China, Stem Cell and Translational Research(2018YFA0109700 to D.-L.H.) and Open Project of Key Laboratory of Genomic and Precision Medicine of the CAS. 摘　　要：Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. To comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, we employed single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases, and identified diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, in PDAC. We found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, we found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, our findings provide a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy. 关 键 词：Pancreatic DUCTAL ADENOCARCINOMA (PDAC) RNA-SEQ TRANSCRIPTION factors (TFs)
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