Abstract
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.
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Data availability
The accession number for the sequencing data reported in this paper is GSA: CRA001160. These data have been deposited in the Genome Sequence Archive under project PRJCA001063.
Change history
13 August 2019
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Acknowledgements
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.P.Z., 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.-L.H.), 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.
Authorship contributions
Y.P.Z., Y.-G.Y. and W.M.W. conceived this project. J.Y.P., H.C., L.L.L., D.H., J.L.J., G.-S.C, Y.Y., W.Z.W., D.G., M.H.D., J.C.G., T.P.Z., Q.L., Y.L., Y.-L.Z. perform experiments under the supervision of W.M.W. and Y.P.Z. B.-F.S., C.-Y.C., J.-Y.Z. and Y.-S.C. perform bioinformatics analysis under the supervision of D.-L.H. and Y.-G.Y. D.-L.H., Y.P.Z., Y.-G.Y. and W.M.W. wrote the manuscript.
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Peng, J., Sun, BF., Chen, CY. et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res 29, 725–738 (2019). https://doi.org/10.1038/s41422-019-0195-y
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DOI: https://doi.org/10.1038/s41422-019-0195-y
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