Murine models of lung cancer as a platform to investigate cell death

Alterations in programmed cell death pathways play a critical role in cancer development and maintenance. Yet the detailed mechanisms contributing to tumor initiation, progression, and therapeutic response in lung cancer remain incompletely understood. Also, models to study how changes in the cell death machinery impact tumor-immune interactions are limited. To address this, we describe two complementary murine models of lung adenocarcinoma that enable functional interrogation of cell death pathways in vivo. The first model is a clinically relevant, genetically engineered mouse model (GEMM) driven by Kras^G12D activation and Tp53 loss, in which somatic CRISPR-Cas9-mediated gene editing permits tumor cell-specific knockout of candidate genes, facilitates in-depth studies of programmed cell death and immune signaling within 19 weeks. The second approach illustrates how a syngeneic orthotopic transplantation model can be used to study target genes and pathways that influence the tumor microenvironment and immunogenic cell death in a two-week timeframe. Together, these methods provide reproducible and versatile tools to investigate how modulation of cell death pathways impacts lung cancer development and progression and affects the tumor immune microenvironment, thus providing important information to guide the development of novel therapeutic strategies in lung cancer.