A Syngeneic Immunocompetent Mouse Model of Gallbladder Cancer Reveals Tumorigenesis and Therapeutic Response

2025 · doi:10.1101/2025.11.17.687512
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This paper developed a novel syngeneic, immunocompetent mouse model of gallbladder cancer by engineering a murine gallbladder organoid–derived cell line (mGBC1-ZH) with Kras and Trp53 mutations and testing tumor growth after subcutaneous and orthotopic implantation in C57BL/6J mice. The authors used RNA-seq and WES plus histology and functional assays to show that the tumors recapitulate human GBC features, including biliary epithelial differentiation, aggressive pathology, genomic instability patterns, and an immunosuppressive “cold” tumor microenvironment. They identified CXCL5 as upregulated in human GBC and reported that CXCL5 promotes proliferation, metastasis, and neutrophil infiltration in the syngeneic mouse model, while the model remained responsive to gemcitabine and cisplatin, with gene-expression changes tracked during model development. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Purpose Gallbladder cancer (GBC) is a rare but highly lethal malignancy with one of the poorest prognoses among cancers of the digestive system cancers. However, current experimental models of GBC face critical limitations, particularly their dependence on immunodeficient hosts, which precludes the investigation of the tumor microenvironment. We aimed to establish a novel syngeneic immunocompetent mouse model that recapitulates human GBC and enables the investigation of tumor-immune interactions. Experimental Design We engineered a murine cell line (mGBC1-ZH) from normal mouse gallbladder organoids expressing Kras and Trp53 (encoding mouse p53) mutations. Tumorigenic potential of mGBC1-ZH was evaluated by subcutaneous and orthotopic implantation. RNA-Seq and WES was used to demonstrate its characterization and similarity with human GBC. Immunohistochemistry, CCK8, and transwell assays wereused to investigate the role of CXCL5 in GBC. Therapeutic responses to standard first-line chemotherapeutic agents was evaluated in the syngeneic GBC model.

Results

This model supports both subcutaneous and orthotopic tumor growth in immunocompetent C57BL/6J hosts while preserving hallmark features of human GBC, including biliary epithelial differentiation (CK7+/CK19+), aggressive histopathology, and an immunosuppressive “cold” tumor microenvironment. Genomic characterization revealed recurrent chromosomal instability and copy number alterations mirroring human GBC. Comprehensive transcriptomic profiling revealed profound gene expression changes during the model development, and resembled transcriptional features between mGBC1-ZH and human GBC cell lines and samples. CXCL5 was found to be upregulated in human GBC, and promote proliferation, metastasis, and neutrophils infiltration of GBC in the syngeneic mouse model. Functional validation of the syngeneic GBC model demonstrated therapeutic responsiveness to frontline chemotherapeutics gemcitabine and cisplatin with significant in vivo tumor regression.

Conclusions

In summary, we establised a novel syngeneic GBC mouse model, overcoming the limitations of traditional models by enabling studies in immunocompetent hosts. This model provides valuable insights into the molecular evolution from normal gallbladder cells to transformed cancer cells and establishes a robust platform for both mechanistic studies and therapeutic development. Competing Interest Statement A patent application has been filed based on the findings in this paper (Houbao Liu et al. CN202511038362.4). Footnotes RNA-seq analysis of the shNT and shCxcl5 cells of mGBC1-ZH. Tumor growth comparison of CT and Cxcl5-OE cells in C57BL/6J mouse, quantification of H&E, immunohistochemical for Ki-67, Ly6G, and MPO of subcutaneous tumors.

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