Abstract 1321: New mouse models of metastatic lung cancer

Abstract

Abstract INTRODUCTION: Lung cancer is the leading cause of cancer deaths worldwide and greater than 75% of human lung cancer deaths can be attributed to metastasis. Metastatic disease in most existing mouse models of pulmonary adenocarcinoma is typically sporadic and often requires aging mice for several months. These factors limit the usefulness of most current mouse models for basic and pre-clinical research aimed at identifying mechanisms and effective treatments of metastatic disease. We have developed two novel mouse models of metastatic lung cancer and report here on changes in protein expression and immune cell recruitment in the lungs of these models. METHODS AND RESULTS: Mouse models were generated by adding mutations in Dicer1, an RNAse III enzyme within the microRNA (miRNA) biosynthesis pathway, to a mouse model of Kras-driven pulmonary adenocarcinoma. For both models, tumorigenesis was induced by conditional expression of an oncogenic allele of Kras (KrasG12D), deletion of both alleles of Trp53 and deletion of one allele of Dicer1 in one cell type and the expression of a truncated Dicer1 allele in a different cell type. In the absence of Dicer1 truncation, mice expressing KrasG12D and deleting Trp53 in club cells have a reported median survival of 28.6 weeks after tumor induction. We detected accelerated development of pulmonary adenocarcinoma and lymph node metastasis (12.1 weeks) only when we induced tumorigenesis in club cells and truncated DICER1 in alveolar type II (ATII) cells. Induction of tumorigenesis in ATII cells and truncation of DICER1 in club cells did not accelerate tumorigenesis or metastasis. To evaluate the molecular and cellular changes in the different phenotypes of these models we have characterized protein expression, using spatial proteomics, and immune cell recruitment, using flow cytometry. CONCLUSIONS: Through cell type specific truncation/deletion of Dicer1 we have generated a new mouse model that rapidly develops pulmonary adenocarcinomas and metastatic disease. Our findings support our hypothesis that tumorigenesis and metastasis are influenced by miRNA regulated communication between different cell types. Preliminary flow cytometry and spatial proteomic analyses have suggested cellular targets underlying phenotypic differences between our two mouse models. These models have potential for both understanding the basic processes of metastasis and for pre-clinical studies aimed at preventing and/or treating metastatic lung cancer. Citation Format: Paige Ramkissoon, Julie Wells, Richard S. Maser, Jiayuan Shi, Zheng Gong, Qing Li, Brian Hoffmann, Anne Marchini, Elaine Bechtel, Rosalinda Doty, Gary Ren, Carol J. Bult. New mouse models of metastatic 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 1321.