Author:
Tong Yexin,Sun Mingjun,Chen Lingli,Wang Yunzhi,Li Yan,Li Lingling,Zhang Xuan,Cai Yumeng,Qie Jingbo,Pang Yanrui,Xu Ziyan,Zhao Jiangyan,Zhang Xiaolei,Liu Yang,Tian Sha,Qin Zhaoyu,Feng Jinwen,Zhang Fan,Zhu Jiajun,Xu Yifan,Lou Wenhui,Ji Yuan,Zhao Jianyuan,He Fuchu,Hou Yingyong,Ding Chen
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.
Funder
National Key R&D Program of China
National Natural Science Foundation of China
Shanghai Municipal Science and Technology Major Project
Major Project of Special Development Funds of Zhangjiang National Independent innovation Demonstration Zone
China Postdoctoral Science Foundation
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Biology,Hematology
Cited by
8 articles.
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