Integrative proteogenomic analysis provides molecular insights and clinical significance in gallbladder cancer

Zile Fu; Yuanli Song; Fen Liu; Lv Chen; Shangli Cai; Peng Cui; Guoqiang Wang; Wenchuan Xie; Shu Zhang; Li Ding; Pei Wang; Bing Zhang; Henry Rodriguez; Feiling Feng; Xufeng Zhang; Wei Gong; Qiang Gao; Daming Gao; Hu Zhou; Jia Fan

doi:10.1016/j.ccell.2025.12.014

Integrative proteogenomic analysis provides molecular insights and clinical significance in gallbladder cancer

Cancer Cell. 2026 Feb 9;44(2):405-423.e13. doi: 10.1016/j.ccell.2025.12.014. Epub 2026 Jan 8.

Authors

Zile Fu¹, Yuanli Song², Fen Liu³, Lv Chen¹, Shangli Cai⁴, Peng Cui⁴, Guoqiang Wang⁴, Wenchuan Xie⁴, Shu Zhang¹, Li Ding⁵, Pei Wang⁶, Bing Zhang⁷, Henry Rodriguez⁸, Feiling Feng⁹, Xufeng Zhang¹⁰, Wei Gong¹¹, Qiang Gao¹², Daming Gao¹³, Hu Zhou¹⁴, Jia Fan¹⁵

Affiliations

¹ Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China.
² Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China.
⁴ Burning Rock Biotech, Guangdong 510300, China.
⁵ Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University, St. Louis, MI 63108, USA.
⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷ Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁸ Office of Cancer Clinical Proteomics Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁹ Department of Biliary Tract Surgery I, Third Affiliated Hospital of Naval Medical University (Eastern Hepatobiliary Surgery Hospital), Shanghai 201805, China.
¹⁰ Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
¹¹ Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Electronic address: gongwei@xinhuamed.com.cn.
¹² Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai 200433, China. Electronic address: gaoqiang@fudan.edu.cn.
¹³ Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, 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.
¹⁴ 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. Electronic address: zhouhu@simm.ac.cn.
¹⁵ Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address: fan.jia@zs-hospital.sh.cn.

PMID: 41512870
DOI: 10.1016/j.ccell.2025.12.014

Abstract

Gallbladder cancer (GBC) is a highly aggressive malignancy with dismal outcomes. To dissect its molecular characteristics and identify potential therapeutic avenues, we performed proteogenomic characterization of 195 tumors and 135 adjacent non-cancerous gallbladder tissues. Integrative analyses highlighted TP53 and ELF3 mutations as key drivers disrupting signaling and metabolism. ErbB2 amplification, a pivotal genomic event, was associated with reduced canonical PI3K/AKT and RAS/MAPK/ERK signaling yet enhanced proliferative activity. We discovered potential gain-of-function mutations in ErbB2 and ErbB3 predicted to enhance ErbB2-ErbB3 heterodimer activity. ACAT1 and PHGDH were identified as metabolic drivers of GBC liver invasion. Integrated molecular and immune subtyping delineated four distinct multi-omics and immune microenvironment subtypes, each carrying prognostic and therapeutic relevance. Although rare, neuroendocrine GBC was separately characterized, revealing MEIS1 as a potential regulator of neuroendocrine-like features. Together, this study establishes a proteogenomic landscape of GBC, providing biological insights and guiding future translational efforts.

Keywords: gallbladder cancer; immune subtypes; multi-omics subtypes; proteogenomics.

MeSH terms

Aged
Clinical Relevance
DNA-Binding Proteins / genetics
Erb-b2 Receptor Tyrosine Kinases / genetics
Erb-b2 Receptor Tyrosine Kinases / metabolism
Female
Gallbladder Neoplasms* / genetics
Gallbladder Neoplasms* / metabolism
Gallbladder Neoplasms* / pathology
Humans
Male
Middle Aged
Mutation
Prognosis
Proteogenomics* / methods
Proto-Oncogene Proteins c-ets / genetics
Receptor, ErbB-3
Signal Transduction
Transcription Factors / genetics
Tumor Microenvironment
Tumor Suppressor Protein p53 / genetics

Substances

Erb-b2 Receptor Tyrosine Kinases
ERBB2 protein, human
ERBB3 protein, human
Proto-Oncogene Proteins c-ets
Transcription Factors
Tumor Suppressor Protein p53
DNA-Binding Proteins
TP53 protein, human
Receptor, ErbB-3