Hydrogel‐Embedded Precision‐Cut Lung Slices Model Lung Cancer Premalignancy Ex Vivo

Abstract Lung cancer is the leading global cause of cancer‐related deaths. Although smoking cessation is the best prevention, 50% of lung cancer diagnoses occur in people who have quit smoking. Research into treatment options for high‐risk patients is constrained to rodent models, which are time‐consuming, expensive, and require large cohorts. Embedding precision‐cut lung slices (PCLS) within an engineered hydrogel and exposing this tissue to vinyl carbamate, a carcinogen from cigarette smoke, creates an in vitro model of lung cancer premalignancy. Hydrogel formulations are selected to promote early lung cancer cellular phenotypes and extend PCLS viability to six weeks. Hydrogel‐embedded PCLS are exposed to vinyl carbamate, which induces adenocarcinoma in mice. Analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content after six weeks reveals that vinyl carbamate induces premalignant lesions with a mixed adenoma/squamous phenotype. Putative chemoprevention agents diffuse through the hydrogel and induce tissue‐level changes. The design parameters selected using murine tissue are validated with hydrogel‐embedded human PCLS and results show increased proliferation and premalignant lesion gene expression patterns. This tissue‐engineered model of human lung cancer premalignancy is the foundation for more sophisticated ex vivo models that enable the study of carcinogenesis and chemoprevention strategies.