There is a critical need to identify strategies for lung cancer prevention, as it remains the leading cause of cancer-related death in the US. A critical barrier to developing new approaches to prevent lung cancer is the lack of understanding of key molecular and cellular changes that lead to cancer initiation and progression. Our group has initiated a Pre-Cancer Genome Atlas (PCGA) to define the early molecular alterations that drive premalignant progression of lung cancer. This work has identified transcriptomic alterations in immune pathways associated with progression of bronchial dysplasia (BD) that werefurther validated by immunofluorescent staining showing shifts in immune populations in adjacent bronchial biopsy sections. A challenge to further explore interactions between epithelial and immune cells driving lesion progression is the lack of in vivo models of premalignant transitions ofBD that progress into lung squamous cell carcinoma (LUSC). However, in the NTCU mouse model of LUSC, mice treated with carcinogen develop lesions histologically comparable to human BD. The NTCU-induced murine model serves to act as a robust model for LUSC premalignancy, however, the molecular and cellular alterations driving disease in this model have not been well characterized. This study seeks to investigate the molecular pathogenesis of NTCU-induced BD progression to carcinoma to that of human BD progression to determine the pre-clinical utility of the model for intervention studies.

RNA was isolated from normal, dysplastic and tumor tissue from NTCU-treated mice and sequenced (n=22). Gene expression alterations associated with histological grade were identified using regression models. Concordance between the murine and human data was investigated using GSEA (Gene Set Enrichment Analysis). We identified 503 genes differentially expressed with increasing histological severity in the mouse dysplasia (FDR<0.05) and involved in cancer signaling and immune regulation. We also identified significant concordance of gene expression differences associated with histology between mouse and human dysplastic lesions (FDR<0.05). Furthermore, fluorescent cytometry analysis of lung leucocytes detected immune cell infiltration associated with increasing dose anddisease progression (n=30), and identified a dose-dependent suppression of several lymphoid populations and increase in myeloid populations frequencies associated with disease progression. These observations were concordant with transcriptional and histologic findings in both mouse and human samples. In summary, our data suggest molecular and cellular concordance between human and murine lesions that precede the development of LUSC, and suggest NTCU-induced BD progression to LUSC be a relevant pre-clinical model for testing targeted immunoprevention strategies.

Citation Format: Sarah A. Mazzilli, Kahkeshan Hijazi, Riley Pihl, Anna Belkina, Xiaohui Zhang, Gang Liu, Marc Lenburg, Christopher Stevenson, Avrum Spira, Jennifer Beane. The molecular characterization of a murine lung premalignancy model for lung cancer interception [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 660.