Abstract 5182: Transcriptomic analysis of mouse models of lung adenocarcinoma with different metastatic phenotypes

Introduction: Lung cancer is the leading cause of cancer deaths worldwide with most deaths attributed to metastatic disease. Existing mouse models of lung adenocarcinoma (LUAD) rarely become metastatic, limiting their usefulness for basic and pre-clinical research aimed at identifying mechanisms of metastatic disease. We have developed two novel mouse models of LUAD, KPDT-1 and KPDT-2, that feature cell type-specific inducible oncogenic KrasG12D, loss of Trp53 function, and deleted/truncated Dicer1. The survival times, rate of tumor progression, and metastatic phenotypes of these models depend on the cell types that harbor the genetic alterations. We performed transcriptomics (mRNA and microRNA) to investigate the molecular and cellular drivers underlying the observed differences in the models. Methods and Results: KPDT-1 and KPDT-2 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 LUAD. For KPDT-1, tumorigenesis was induced by conditional expression of an oncogenic KrasG12D allele, deletion of both alleles of Trp53 and deletion of one allele of Dicer1 in club cells and the expression of a truncated Dicer1 allele in alveolar type II (ATII) cells. In KPDT-2 animals, the cell types were reversed. We observed decreased survival, accelerated tumor progression, and enhanced lymph node metastasis only in KPDT-1 animals. Induction of tumorigenesis in ATII cells and truncation of Dicer1 in club cells (KPDT-2) did not accelerate tumor progression. Differential expression analysis using DESeq2 revealed 206 differentially expressed genes and 45 differentially expressed microRNAs between the two models. Term enrichment analyses showed that genes upregulated in KPDT-1 animals are associated with microtubule movement and organization. The upregulated genes of KPDT-2 animals are enriched in functions related to metabolism. Six microRNAs were upregulated in the KPDT-1 model. These miRNAs were reported previously as being differentially expressed in other cancers, and 4 of them (miR-92a-3p, miR-542-5p, miR-449a-5p, and miR-296-5p) have been linked previously to metastasis. Conclusions: Through cell type-specific truncation/deletion of Dicer1, we have generated a new mouse model that rapidly develops Kras/Trp53-driven LUAD and metastatic disease. Our findings suggest that tumorigenesis and metastasis are influenced by miRNA-mediated communication between different cell types. Further investigation into the pathways involved in these models will give more insight into miRNA-mediated tumorigenesis and the underlying mechanisms of metastasis. We will continue to develop these models to support investigation of molecular mechanisms underlying metastasis. Citation Format: Naomi Mitchell-Hutchinson, Paige Ramkissoon, Julie Wells, Rick Maser, Tim Stodola, Brian Hoffman, Anne Marchini, Elaine Bechtel, Rosalinda Doty, Carol Bult. Transcriptomic analysis of mouse models of lung adenocarcinoma with different metastatic phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5182.