Abstract 7227: An inducible, spatially restricted mouse model of lung cancer

Abstract Accurately modeling human lung tumor initiation and progression in genetically engineered mouse models (GEMMs) remains a challenge. In contrast to human lung cancer development, where patients typically present with a solitary tumor nodule, the majority of GEMMs produce numerous independent primary lung lesions. Each of these lesions then evolves as an independent tumor, a situation not relevant to human lung cancer biology. The Cre-loxP recombination system is widely used to generate GEMMs, including the inducible, tamoxifen-dependent systems that allow cell-specific conditional activation via promoter regulation. We have used this system extensively to generate KRAS-driven Lung adenocarcinomas arising from club cells via the club cell secretory protein (CCSP) Cre-ERT2 system. While powerful, this model has limitations. Specifically, limiting tumor induction to a single location within the lung is impossible. To address this limitation, we have combined the highly efficient photoactivable Cre (PA-Cre) recombinase mouse (JAX: 033544) with a novel CCSP-FlpO mouse to spatially limit tumor formation based on targeted blue-light exposure. Exploiting the CCSP promoter enables us to limit FlpO recombinase expression to club cells, thereby confining the two light-activatable Cre halves to club cells. Following focal trans-cutaneous blue light exposure, the PA -Cre halves dimerize and induce the oncogenic alleles, KRAS p.G12D, and Serine Threonine Kinase 11 loss, respectively. We assert that utilizing this approach will overcome major limitations inherent in current GEMMs used to study lung cancer and provide a paradigm-shifting platform to study lung cancer initiation and progression. Citation Format: Israel Ifeoluwa Odekunle, Sydney Remington, Allison Racela, David J. Seward. An inducible, spatially restricted mouse model of lung cancer [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 7227.