Lung cancer is the leading cause of cancer-related deaths in the United States and represents approximately 14% of all new cancer diagnoses. Survival rates have changed little in recent decades in spite of new chemotherapeutic and targeted molecular agents and advances in surgical treatment. Our lung cancer research efforts aim to gain a better understanding of human lung cancer biology by establishing biomimetic three-dimensional culture models that more closely resemble the microenvironment that cancer cells experience in vivo. We take advantage of decellularized whole-lung scaffolds to establish biomimetic culture conditions of established lung cancer cell lines or primary human lung cancer cells. We seek to understand how a three-dimensional organization in the natural environment of decellularized lung scaffolds affects human lung cancer behavior, its interactions with the extracellular matrix and other cells in the microenvironment, the activation of specific oncogenic pathways, and the response to cytotoxic chemotherapy and targeted molecular therapies. These models have the potential to provide new strategies for the treatment of lung cancer and expedite clinical translation. This project benefits from expertise in molecular biology, cancer biology, imaging, and biomedical engineering.