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.