Characterization of a bronchoscopically induced transgenic lung cancer pig model for human translatability.

There remains a need for animal models with human translatability in lung cancer (LC) research. Findings in pigs can have a substantial impact owing to their similar anatomy and physiology to humans. Here we present a bronchoscopically induced LC model in Oncopigs carrying inducible KRASG12D and TP53R167H mutations. A total of 12 Oncopigs underwent 29 injections via flexible bronchoscopy: 18 adenovirus-Cre recombinase gene (AdCre) inductions were performed endobronchially (n = 6) and transbronchially (n = 12), and 11 control injections were performed without AdCre. Oncopigs underwent serial chest CT with clinical follow-up for 29 weeks. Lung and organ tissues underwent histopathology, immunohistochemistry and RNA sequencing with comparative analysis to human LC data. All 18 sites of AdCre injections had lung consolidations on computed tomography imaging. Inductions led to an overall success rate of 77.8%, including both invasive cancer (61.1%) and carcinoma in situ (16.7%). Transbronchial injections led to histopathologic invasive cancer and/or carcinoma in situ in 11/12 (91.7%) and invasive cancer in 8/12 (66.6%). Endobronchial inductions led to invasive cancer in 3/6 (50%). A soft tissue metastasis was observed in one Oncopig. Immunohistochemistry confirmed the expression of Pan-Cytokeratin (Pan-CK)+ in epithelial cancer cells, with macrophage and T cell infiltration in the tumor microenvironment. Transcriptome comparison showed 54.3% overlap with human LC, while KRAS-mutant mouse LC had 29.88% overlap with human LC. The immunocompetent Oncopig model has a high rate of LC following bronchoscopic transbronchial induction. An overlap of the Oncopig LC transcriptome with the human LC transcriptome was noted. This pig model of LC is expected to have high clinical translatability.