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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2022

Open Access 01-12-2022 | Metastasis | Research

Proteogenomic insights into the biology and treatment of pancreatic ductal adenocarcinoma

Authors: 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

Published in: Journal of Hematology & Oncology | Issue 1/2022

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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.
Appendix
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Metadata
Title
Proteogenomic insights into the biology and treatment of pancreatic ductal adenocarcinoma
Authors
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
Publication date
01-12-2022
Publisher
BioMed Central
Keyword
Metastasis
Published in
Journal of Hematology & Oncology / Issue 1/2022
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-022-01384-3

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