Proteogenomic Analysis Provides Molecular Insights In Gallbladder Cancer
Researchers from Fudan University, the Shanghai Institute of Biochemistry and Cell Biology, the Shanghai Institute of Materia Medica, and the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) have assembled one of the most detailed molecular portraits of gallbladder cancer (GBC) to date. The team integrated genomic, transcriptomic, proteomic, and phosphoproteomic data from nearly 200 tumors and adjacent normal tissues (NATs) to uncover new therapeutic leads. Their work was published in Cancer Cell.
Whole-exome sequencing revealed that TP53 (47.9%) and ELF3 (9.0%) were among the most commonly altered driver genes across all samples. TP53 mutations were associated with cell cycle activation and loss of cell adhesion, whereas ELF3 mutations correlated with metabolic reprogramming, including shifts toward glycolysis, oxidative phosphorylation, and fatty acid oxidation.
Alterations to the ErbB signaling family (EGFR, ERBB2, ERBB3, ERBB4) were present in over 45% of tumors, and some ErbB-driven mechanisms defied canonical expectations. For example, ERBB2 gene amplification led to suppression of PI3K/AKT and RAS/MAPK/ERK signaling compared to adjacent normal tissues; this is the reverse of what is seen in some other cancer types, including breast and gastric cancers.
In a similar vein, the team observed several previously unreported mutations that increased ERBB2–ERBB3 receptor pair signaling, activating the stress-response kinase JNK rather than the growth pathways typically associated with ErbB signaling. Taken together, these observations suggest that ErbB signaling may be "rewired" in GBC.
Liver invasion affects nearly two-thirds of GBC patients and worsens prognosis substantially. Proteomic profiling of matched primary tumor and liver invasion lesions from 18 patients found that ACAT1 and PHGDH expression were consistently elevated at invasion sites. In cell line experiments, silencing either gene reduced both proliferation and invasive capacity.
Analysis of the tumor immune microenvironment across all 193 patients identified four subtypes with significantly different survival outcomes: immune-desert, immune-active, CAF-dominant, and immunosuppressive. Chromosome 18q deletion was associated with reduced immune activity across multiple subtypes, correlating with depletion of CD8+ T cells, NK cells, and M1 macrophages.
A parallel effort based on all molecular data layers defined four tumor-intrinsic subtypes, each defined by a dominant biological feature: cell cycle activity (MO1), oncogenic signaling (MO2), metabolic programming (MO3), and ERBB2-driven glycosylation (MO4). Drug testing in patient-derived organoids showed responses that matched predicted subtype vulnerabilities.
Ultimately, these findings highlight the potential for subtype-specific strategies to improve outcomes for patients with GBC. The identification of novel functional targets, alongside the development of a subtyping framework for GBC, provides a foundation for future research and holds promise for guiding precision therapy.
Proteomic (PDC000606) and phosphoproteomic (PDC000607) data from this study are available via the Proteomic Data Commons.