Characterization of A Bronchoscopically Induced Transgenic Lung Cancer Pig Model for Human Translatability

TL;DR

This study introduces a pig model for lung cancer that closely mimics human lung cancer, with high translatability due to similar anatomy and genetic overlap.

Contribution

The novel contribution is the development and characterization of a bronchoscopically-induced transgenic lung cancer pig model with high human translatability.

Findings

Transbronchial injections led to invasive cancer in 66.6% of Oncopigs.

The Oncopig lung cancer transcriptome showed 54.3% overlap with human lung cancer data from TCGA.

The model is immunocompetent and exhibits tumor microenvironment features like macrophage and T cell infiltration.

Abstract

There remains a need for animal models with human translatability in lung cancer (LC) research. Findings in pigs have high impact on humans due to similar anatomy and physiology. We present the characterization of a bronchoscopically-induced LC model in Oncopigs carrying inducible KRASG12D and TP53R167H mutations.

Twelve Oncopigs underwent 29 injections via flexible bronchoscopy. Eighteen Adenovirus-Cre recombinase gene (AdCre) inductions were performed endobronchially (n = 6) and transbronchially with a needle (n = 12). Eleven control injections were performed without AdCre. Oncopigs underwent serial contrast-enhanced chest CT with clinical follow-up for 29 weeks. Following autopsy, lung and organ tissues underwent histopathology, immunohistochemistry, and RNA-sequencing with comparative analysis with The Cancer Genome Atlas (TCGA) human LC data.

All 18 sites of AdCre injections had lung consolidations on CT imaging. Transbronchial injections led to histopathologic invasive cancer and/or carcinoma in situ (CIS) in 11/12 (91.7%), and invasive cancer (excluding CIS) 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 expression of Pan-CK+/epithelial cancer cells, with macrophages and T cells infiltration in the tumor microenvironment. Transcriptome comparison showed 54.3% overlap with human LC (TCGA), in contrast to 29.88% overlap of KRAS-mutant mouse LC with human LC.

The transgenic and immunocompetent Oncopig model has a high rate of LC following bronchoscopic transbronchial induction. Overlap of the Oncopig LC transcriptome with human LC transcriptome was noted. This pig model is expected to have high clinical translatability to the human LC patient.

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