PT - JOURNAL ARTICLE AU - Rachel Blomberg AU - Kayla Sompel AU - Caroline Hauer AU - Brisa Peña AU - Jennifer Driscoll AU - Patrick S. Hume AU - Daniel T. Merrick AU - Meredith A. Tennis AU - Chelsea M. Magin TI - Tissue-engineered models of lung cancer premalignancy AID - 10.1101/2023.03.15.532835 DP - 2023 Jan 01 TA - bioRxiv PG - 2023.03.15.532835 4099 - http://biorxiv.org/content/early/2023/03/17/2023.03.15.532835.short 4100 - http://biorxiv.org/content/early/2023/03/17/2023.03.15.532835.full AB - Lung cancer is the leading global cause of cancer-related deaths. Although smoking cessation is the best preventive action, nearly 50% of all lung cancer diagnoses occur in people who have already quit smoking. Research into treatment options for these high-risk patients has been constrained to rodent models of chemical carcinogenesis, which are time-consuming, expensive, and require large numbers of animals. Here we show that embedding precision-cut lung slices within an engineered hydrogel and exposing this tissue to a carcinogen from cigarette smoke creates an in vitro model of lung cancer premalignancy. Hydrogel formulations were selected to promote early lung cancer cellular phenotypes and extend PCLS viability up to six weeks. In this study, hydrogel-embedded lung slices were exposed to the cigarette smoke derived carcinogen vinyl carbamate, which induces adenocarcinoma in mice. At six weeks, analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content revealed that vinyl carbamate induced the formation of premalignant lesions with a mixed adenoma/squamous phenotype. Two putative chemoprevention agents were able to freely diffuse through the hydrogel and induce tissue-level changes. The design parameters selected using murine tissue were validated with hydrogel-embedded human PCLS and results showed increased proliferation and premalignant lesion gene expression patterns. This tissue-engineered model of human lung cancer premalignancy is the starting point for more sophisticated ex vivo models and a foundation for the study of carcinogenesis and chemoprevention strategies.Competing Interest StatementThe authors have declared no competing interest.