Journal of Hematology & Oncology (Nov 2022)
Proteogenomic insights into the biology and treatment of pancreatic ductal adenocarcinoma
- Yexin Tong,
- Mingjun Sun,
- Lingli Chen,
- Yunzhi Wang,
- Yan Li,
- Lingling Li,
- Xuan Zhang,
- Yumeng Cai,
- Jingbo Qie,
- Yanrui Pang,
- Ziyan Xu,
- Jiangyan Zhao,
- Xiaolei Zhang,
- Yang Liu,
- Sha Tian,
- Zhaoyu Qin,
- Jinwen Feng,
- Fan Zhang,
- Jiajun Zhu,
- Yifan Xu,
- Wenhui Lou,
- Yuan Ji,
- Jianyuan Zhao,
- Fuchu He,
- Yingyong Hou,
- Chen Ding
Affiliations
- Yexin Tong
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Mingjun Sun
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Lingli Chen
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Yunzhi Wang
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Yan Li
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Lingling Li
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Xuan Zhang
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Yumeng Cai
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Jingbo Qie
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Yanrui Pang
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Ziyan Xu
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Jiangyan Zhao
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Xiaolei Zhang
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Yang Liu
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Sha Tian
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Zhaoyu Qin
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Jinwen Feng
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Fan Zhang
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Jiajun Zhu
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Yifan Xu
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Wenhui Lou
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Yuan Ji
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Jianyuan Zhao
- Institute for Development and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
- Fuchu He
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Yingyong Hou
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- Chen Ding
- Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Human Phenome Institute, Department of Pathology, Department of General Surgery, Zhongshan Hospital, Fudan University
- DOI
- https://doi.org/10.1186/s13045-022-01384-3
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 47
Abstract
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis. Proteogenomic characterization and integrative proteomic analysis provide a functional context to annotate genomic abnormalities with prognostic value. Methods We performed an integrated multi-omics analysis, including whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis of 217 PDAC tumors with paired non-tumor adjacent tissues. In vivo functional experiments were performed to further illustrate the biological events related to PDAC tumorigenesis and progression. Results A comprehensive proteogenomic landscape revealed that TP53 mutations upregulated the CDK4-mediated cell proliferation process and led to poor prognosis in younger patients. Integrative multi-omics analysis illustrated the proteomic and phosphoproteomic alteration led by genomic alterations such as KRAS mutations and ADAM9 amplification of PDAC tumorigenesis. Proteogenomic analysis combined with in vivo experiments revealed that the higher amplification frequency of ADAM9 (8p11.22) could drive PDAC metastasis, though downregulating adhesion junction and upregulating WNT signaling pathway. Proteome-based stratification of PDAC revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Immune clustering defined a metabolic tumor subset that harbored FH amplicons led to better prognosis. Functional experiments revealed the role of FH in altering tumor glycolysis and in impacting PDAC tumor microenvironments. Experiments utilizing both in vivo and in vitro assay proved that loss of HOGA1 promoted the tumor growth via activating LARP7-CDK1 pathway. Conclusions This proteogenomic dataset provided a valuable resource for researchers and clinicians seeking for better understanding and treatment of PDAC.
Keywords
