Abstract 927: Developing new mouse models of metastatic lung cancer

Abstract

Abstract INTRODUCTION: The focus of this work is to develop new mouse models for metastatic lung cancer. 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 mouse models for basic and pre-clinical research aimed at identifying effective treatments of metastatic disease. METHODS AND RESULTS: We have developed new mouse models of pulmonary adenocarcinoma in which we added 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, we induced tumorigenesis by conditionally expressing an oncogenic allele of Kras (KrasG12D), deleting of both alleles of Trp53 and deleting one allele of Dicer1 in one cell population then expressing truncated Dicer1 in a different cell population. 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. When we also deleted one allele of Dicer1 in Club cells and truncated Dicer1 in alveolar type II cells of these mice, they exhibited respiratory distress and began dying 12.1 weeks after tumor induction. In our initial pilot study, all animals (12/12) developed pulmonary adenocarcinoma and 30% (3/10) had lymph node metastasis. We did not observe accelerated tumorigenesis, however, when we switched cell types, inducing tumorigenesis in alveolar type II cells and truncating Dicer1 in Club cells, or when induced tumorigenesis and truncating Dicer1 within the same cell populations. 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. 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: Julie Wells, Richard Maser, Ashley Tucker, Teresa McGee, Wendy Memishian, Rosalinda Doty, Carol J. Bult. Developing new mouse models of metastatic lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 927.