Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity

Xiaohan Shi, Yunguang Li, Qiuyue Yuan, Shijie Tang, Shiwei Guo, Yehan Zhang, Juan He, Xiaoyu Zhang, Ming Han, Zhuang Liu, Yiqin Zhu, Suizhi Gao, Huan Wang, Xiongfei Xu, Kailian Zheng, Wei Jing, Luonan Chen (), Yong Wang (), Gang Jin () and Dong Gao ()
Additional contact information
Xiaohan Shi: Second Military Medical University (Naval Medical University)
Yunguang Li: Chinese Academy of Sciences
Qiuyue Yuan: Chinese Academy of Sciences
Shijie Tang: Chinese Academy of Sciences
Shiwei Guo: Second Military Medical University (Naval Medical University)
Yehan Zhang: Chinese Academy of Sciences
Juan He: Chinese Academy of Sciences
Xiaoyu Zhang: Chinese Academy of Sciences
Ming Han: Chinese Academy of Sciences
Zhuang Liu: Chinese Academy of Sciences
Yiqin Zhu: Chinese Academy of Sciences
Suizhi Gao: Second Military Medical University (Naval Medical University)
Huan Wang: Second Military Medical University (Naval Medical University)
Xiongfei Xu: Second Military Medical University (Naval Medical University)
Kailian Zheng: Second Military Medical University (Naval Medical University)
Wei Jing: Second Military Medical University (Naval Medical University)
Luonan Chen: Chinese Academy of Sciences
Yong Wang: Chinese Academy of Sciences
Gang Jin: Second Military Medical University (Naval Medical University)
Dong Gao: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Chromatin accessibility plays an essential role in controlling cellular identity and the therapeutic response of human cancers. However, the chromatin accessibility landscape and gene regulatory network of pancreatic cancer are largely uncharacterized. Here, we integrate the chromatin accessibility profiles of 84 pancreatic cancer organoid lines with whole-genome sequencing data, transcriptomic sequencing data and the results of drug sensitivity analysis of 283 epigenetic-related chemicals and 5 chemotherapeutic drugs. We identify distinct transcription factors that distinguish molecular subtypes of pancreatic cancer, predict numerous chromatin accessibility peaks associated with gene regulatory networks, discover regulatory noncoding mutations with potential as cancer drivers, and reveal the chromatin accessibility signatures associated with drug sensitivity. These results not only provide the chromatin accessibility atlas of pancreatic cancer but also suggest a systematic approach to comprehensively understand the gene regulatory network of pancreatic cancer in order to advance diagnosis and potential personalized medicine applications.

Date: 2022
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DOI: 10.1038/s41467-022-29857-6

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