Within the scope of this project, a 3D, biomimetic model of the lung tumor microenvironment has been established. In order to develop an organotypic biomaterial for use in lung tissue engineering, native lungs were decellularized via several methods and reconstituted into cyto-compatible hydrogels. These hydrogels were demonstrated to support viability and growth of lung tumor cells, healthy bronchial epithelial cells as well as lung organoids. Then organotypic double-network hydrogels were engineered which allow tunability of mechanical properties as well as cell instructive ligands. In these models, it was shown that lung tumor growth and invasive phenotype are regulated via a synergy of mechanical and biochemical extracellular cues. The project demonstrated that the effect of tissue stiffening, a hallmark of many tumor types, is dependent on the composition of the tissue matrix. Stiffness was shown to have opposing effects on cells in organotypic matrices when compared with tumor-mimetic matrices. Furthermore, drug responses of lung tumor cells within 3D biomimetic hydrogels were investigated. The study reveals that 3D drug responses of tumor cells are significantly different than cells cultured as monolayers. Moreover, presenting instructive cues in the extracellular microenvironment that mimic tumor tissues affect drug responses of lung tumor cells in 3D. The project examined whether tumor matrices affect how tumor cells interact with other cell types in the tumor microenvironment. It was found that tumor matrix characteristics play a vital role in regulation of cellular crosstalk in tumors. Lastly, the engineered hydrogels were established as a culturing platform for patient-derived lung tumor organoids which allowed long-term culturing of organoids. During the action, one peer-reviewed publication was produced, two oral presentations at international conferences were delivered, four invited talks at seminars/workshops were given.
