Proteogenomic characterization of non-functional pancreatic neuroendocrine tumors unravels clinically relevant subgroups

Shunrong Ji¹, Lihua Cao², Jing Gao³, Yang Du², Zeng Ye¹, Xin Lou¹, Fen Liu⁴, Yehan Zhang⁵, Junfeng Xu⁶, Xiaohan Shi⁷, Huan Wang⁷, Penghao Li⁷, Yikai Li⁷, Hongxu Chen³, Zhicheng Yang⁸, Suizhi Gao⁷, Wuhu Zhang⁶, Dan Huang⁹, Shujuan Ni⁹, Miaoyan Wei⁶, Fei Wang⁶, Yan Wang⁶, Tian Ding⁶, Desheng Jing⁶, Guixiong Fan⁶, Zhiyun Gong¹⁰, Renquan Lu¹⁰, Yi Qin⁶, Jie Chen¹¹, Xiaowu Xu⁶, Pei Wang¹², Bing Zhang¹³, Li Ding¹⁴, Ana I Robles¹⁵, Henry Rodriguez¹⁵, David K Chang¹⁶, Ralph H Hruban¹⁷, Dong Gao⁵, Daming Gao¹⁸, Gang Jin¹⁹, Hu Zhou²⁰, Jianmin Wu²¹, Xianjun Yu²²

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
² State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing 100142, China.
³ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
⁵ Key Laboratory of Multi-Cell Systems, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
⁶ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.
⁷ Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
⁸ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China.
⁹ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
¹⁰ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
¹¹ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
¹² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029, USA.
¹³ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Medicine, McDonnell Genome Institute, Washington University, St. Louis, MO 63108, USA.
¹⁵ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA.
¹⁶ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
¹⁷ The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA.
¹⁸ Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: dgao@sibcb.ac.cn.
¹⁹ Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China. Electronic address: jingang@smmu.edu.cn.
²⁰ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: zhouhu@simm.ac.cn.
²¹ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing 100142, China; Peking University International Cancer Institute, Peking University, Beijing 100191, China. Electronic address: wujm@bjmu.edu.cn.
²² Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. Electronic address: yuxianjun@fudanpci.org.

PMID: 40185092
DOI: 10.1016/j.ccell.2025.03.016

Proteogenomic characterization of non-functional pancreatic neuroendocrine tumors unravels clinically relevant subgroups

Shunrong Ji et al. Cancer Cell. 2025.

. 2025 Apr 14;43(4):776-796.e14.

doi: 10.1016/j.ccell.2025.03.016. Epub 2025 Apr 3.

Authors

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
² State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing 100142, China.
³ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
⁵ Key Laboratory of Multi-Cell Systems, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
⁶ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.
⁷ Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
⁸ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China.
⁹ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
¹⁰ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
¹¹ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
¹² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029, USA.
¹³ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Medicine, McDonnell Genome Institute, Washington University, St. Louis, MO 63108, USA.
¹⁵ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA.
¹⁶ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
¹⁷ The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA.
¹⁸ Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: dgao@sibcb.ac.cn.
¹⁹ Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China. Electronic address: jingang@smmu.edu.cn.
²⁰ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: zhouhu@simm.ac.cn.
²¹ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing 100142, China; Peking University International Cancer Institute, Peking University, Beijing 100191, China. Electronic address: wujm@bjmu.edu.cn.
²² Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. Electronic address: yuxianjun@fudanpci.org.

PMID: 40185092
DOI: 10.1016/j.ccell.2025.03.016

Abstract

The majority of neuroendocrine neoplasms in pancreas are non-functional pancreatic neuroendocrine tumors (NF-PanNETs), which exhibit a high occurrence of distant metastases with limited therapeutic options. Here, we perform a comprehensive molecular characterization of 108 NF-PanNETs through integrative analysis of genomic, transcriptomic, proteomic, and phosphoproteomic profiles. Proteogenomic analysis provides functional insights into the genomic driver alterations of NF-PanNETs, revealing a potential mediator of MEN1 alterations using Men1-conditional knockout mice. Machine-learning-based modeling uncovers a three-protein signature as an independent prognostic factor, which is validated by an independent external cohort. Proteomic and phosphoproteomic-based stratification identifies four subtypes with distinct molecular characteristics, immune microenvironments, and clinicopathological features. Drug screening using patient-derived tumor organoids identifies cyclin-dependent kinase (CDK) 5 and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D) as ubiquitous and subtype-specific targets, respectively, with in vivo validation using xenograft models. Together, our proteogenomic analyses illustrate a comprehensive molecular landscape of NF-PanNETs, revealing biological insights and therapeutic vulnerabilities.

Keywords: MEN1 mutations; pancreatic neuroendocrine tumors; prognostic signature; proteogenomics; proteomic subtypes.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Proteogenomic characterization of non-functional pancreatic neuroendocrine tumors unravels clinically relevant subgroups

Affiliations

Proteogenomic characterization of non-functional pancreatic neuroendocrine tumors unravels clinically relevant subgroups

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Medical