Abstract 9: Histological characterization of two genetically engineered mouse models of non-small cell lung cancer

Abstract

Abstract Non-small cell lung cancer (NSCLC) patients exhibit minimal symptoms until late-stage disease, resulting in approximately 80% of patients being diagnosed at advanced stages when the response to therapy is low. Effective pre-clinical models are needed to accurately reflect NSCLC disease progression and improve basic NSCLC research. This work characterizes two genetically engineered mouse models (GEMM) that reflect human NSCLC. These mouse lines utilize a cre recombinase system to induce the expression of two oncogenic mutations (KrasG12D, Trp53fl) in club cells or alveolar epithelial cells based on cell type-specific promoters (Scgb1a1, Sftpc), thereby inducing NSCLC in mice. Furthermore, these mice harbor tumor cell-specific transgenes (GFP, MetRS) for cancer tracking. The MetRS transgene allows tumor cells to incorporate azide-bearing methionine analogs (ANL) into newly synthesized proteins which can then be detected via fluorescent noncanonical amino acid tagging (FUNCAT). Cancer mutations were induced at 6 weeks of age and lung samples were collected for histological analysis at early, mid, and late time points. Histological analysis of the club cell model revealed that hyperplasias are most abundant at the early time point and develop into invasive carcinomas within the bronchioles and alveoli at later time points. Histological scoring of this model showed that tumor burden increased from 28% to 61% of the total lung area after 15 weeks. The alveolar cell model progressed rapidly and exhibited adenocarcinomas and squamous cell carcinomas throughout disease progression. Histological scoring of this model revealed that tumor burden rapidly increased from 55% to 89% of total lung area after 5 weeks. FUNCAT analysis demonstrated that the incorporation of ANL within tumor-bearing mice was cancer-cell-specific. These findings suggest that the GEMM models accurately represent human NSCLC based on their cellular profile, morphology, and localization within the lung. The results also confirm that the tumor cells, and not the normal cells/tissues, are able to incorporate ANL into their proteins via the MetRS transgene. These models have the potential to identify biomarkers of NSCLC progression to improve patient prognosis. *This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. LLNL-ABS-839507. Citation Format: Nicole F. Leon, David Baliu-Rodriguez, Deepa K. Murugesh, Aimy Sebastian, Gabriela G. Loots, Nicholas R. Hum. Histological characterization of two genetically engineered mouse models of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 9.