Engineered 3D tumor microenvironment recapitulating stiffness of lung tissue to explore drug resistance of lung carcinoma

Despite clinical advances, the development of anticancer drugs faces high failure rates owing to cancer drug resistance and insufficient understanding of the native tumor microenvironment. Polymeric hydrogels are promising engineered 3D cancer models owing to their tunable properties and structural similarities to the native extracellular matrix. However, precisely mimicking the native cancer microenvironment remains challenging. In this study, we present interpenetrating polymer network (IPN) hydrogels with independent stiffness control as an engineered 3D lung carcinoma model for drug screening and basic cancer research. These IPN hydrogels are formed via horseradish peroxidase/hydrogen peroxide (H2O2)-mediated dual-crosslinking reactions, showing independently tunable stiffness at various H2O2 concentrations. Using this ability, we create engineered 3D lung cancer models that simulate normal and cancerous lung tissue stiffness with encapsulation of non-small cell lung cancer cells. We perform drug resistance tests using this system and compare the drug responses in various preclinical cancer models in vitro and in vivo. Finally, we investigate the biological mechanism underlying the acquired resistance of lung carcinoma cells to epidermal growth factor receptor inhibitors. In summary, our engineered 3D cancer model can serve as an advanced preclinical platform for drug screening and cancer biology, including the biological mechanisms of acquired drug resistance.