Abstract 5165: Development of a syngeneic mouse model to study small cell lung cancer (SCLC)
Authors: Aarushi Garg, Diego A. Velarde, Mario A. Pulido, Daniel J. Mullen, Chunli Yan, Matthew A. Gladstone, Ite A. Offringa
Journal: Cancer Research (2025)

Abstract Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with limited treatment options and a 5-year survival rate of 8% (American Cancer Society, 2023). Preclinical models are essential for studying SCLC, yet traditional models either lack immune system relevance (when using nude mice with human SCLC samples) or have lengthy tumor development times (when using genetically-engineered models). The genetically-engineered mouse model originally developed in the Berns lab is the homozygously floxed Tp53fl/fl;Rb1fl/fl mouse. SCLC is induced through instillation of adenovirus carrying Cre recombinase into the lungs. It requires 6-8 months for proper SCLC development, limiting the model’s utility for rapid therapeutic testing. This model has been combined with additional genetic hits to accelerate cancer development, but this narrows the diversity of developed SCLC tumors. Here, we aim to create a fast, immune-competent SCLC mouse model using cell lines derived in-house from three Tp53fl/fl;Rb1fl/fl SCLC-induced mice. Two types of cell lines were derived from each of three SCLC mouse lungs: cell lines that grow in suspension (S) or adhere (A) to the dish (477A, 477S, 494A, 494S, 625A, 625S, where the number indicates the mouse and A/S indicates attached/suspension growth, respectively). The different growth types mirror that seen in human SCLC cell lines, which can grow suspended in spheres (“classic” SCLC cell lines) or in loose aggregates that attach to plates (“variant” SCLC cell lines). We performed RNA sequencing to gain insight into the molecular characteristics of the six cell lines. Suspension cell lines express neuroendocrine-related genes and the adherent cell lines express epithelial to mesenchymal transition (EMT)-related genes. We tested different injection modes of the mSCLC cell lines (subcutaneous vs. tail vein) and different numbers of injected cells to optimize tumor formation. 477S and 625S cell lines induced subcutaneous tumors in several weeks. 477, 494, 625 (S) cell lines generated liver metastases in mice when injected via the tail vein. Adherent cell lines did not efficiently form tumors, though they did exhibit deletion of Tp53 and Rb1. We are lentivirally-transducing the cell lines with a luciferase construct to allow in vivo imaging of tumor growth and metastasis. We will use the newly developed mSCLC cell lines to test the effects of immunotherapy following cisplatin-etoposide (CE) chemotherapy. We will focus particularly on the immune response to ELAVL4, which in human patients is associated with improved survival. The mSCLC cell line model will provide a new tool to accelerate the evaluation of novel therapeutic strategies and provide a robust platform for studying SCLC progression in mice. Funding: This work was supported by a Wright Foundation Transformative Cancer GrantAward and the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the NIH/NCI. Citation Format: Aarushi Garg, Diego A. Velarde, Mario A. Pulido, Daniel J. Mullen, Chunli Yan, Matthew A. Gladstone, Ite A. Offringa. Development of a syngeneic mouse model to study small cell lung cancer (SCLC) [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 5165.