Abstract
Abstract The molecular events that drive the development of the premalignant lesions (PMLs) that precede lung squamous cell carcinoma (SCC) are poorly understood. A major limitation to understanding PMLs and developing interventions is the lack of preclinical models to test candidates derived from human studies. Previous work by our group and others suggests that the N-nitroso-tris-chloroethylurea (NTCU) mouse model of lung SCC may be a candidate for modeling human PMLs based on histologic similarities, but its molecular relationship to human disease is limited. In this study, we investigate the transcriptomic similarities between PMLs from the NTCU treated mice and humans. RNA from 40 whole lung sections (curls) and laser capture microdissected (LCM) of PMLs of varying histology from SWR/J and A/J mice treated with NTCU were profiled by RNA-Seq. RNA from 131 human endobronchial biopsies representing analogous histological grades were also profiled by RNA-Seq as part of the Pre-Cancer Genome Atlas (PCGA). Linear modeling was used to identify gene expression differences associated with increasing histological severity, mouse strain and sample type. Concordance of gene expression associated with histology between species was investigated using GSEA and GSVA. Biological pathways were inferred using EnrichR and GSEA. A gene expression signature associated with increasing histological severity across all mouse samples was identified (1195 genes, FDR<0.05), which was concordant with gene expression differences associated with increasing histological severity of human PMLs (FDR<0.05). We identified a 51-gene (p<0.001) and a 178-gene (p<0.001) signatures associated with increasing histology in the all SWR/J and A/J samples respectively. These gene expression signatures are enriched for biological pathways involved in immune modulation, occurring with progressing lesions. Conversely, genes whose expression changed with increasing histology in a model that included only LCM samples (153 genes at p<0.001) revealed epithelial-specific processes including the up-regulation of KRT5 and p63 and loss of TTF1. Additionally, in the LCM samples, we identified up-regulation of genes involved in proliferation including a number of genes involved in cell structure, metabolism, transcription and translation, anti-apoptosis as well as several immunosuppressive genes. The major finding of these studies is that there are molecular similarities between PMLs from human and NTCU treated mice, which suggest that this mouse model may be useful to investigate targeted early intervention to halt or reverse PML progression towards lung cancer. Citation Format: Sarah A. Mazzilli, Anna Tassinari, Xiaohui Xiao, Gang Liu, Samjot Dhillon,, Candace Johnson, Mary Reid, Marc Lenburg, Avrum Spira, Jennifer Beane. A pre-clinical model for lung cancer interception: gene expression similarities between human and mouse bronchial premalignant lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1252. doi:10.1158/1538-7445.AM2017-1252
Published Version
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