A Defined 3D Hydrogel Model Recapitulates Key Transcriptomic Features of Lung Adenocarcinoma

Three-dimensional (3D) culture systems have emerged as powerful tools to model tumor biology and bridge the gap between conventional two-dimensional (2D) assays and in vivo studies. Here, we evaluate a poly(ethylene glycol)-based hydrogel as a simplified yet functionally relevant platform for modeling premalignant lung adenocarcinoma using the A549 cell line. Cells cultured in hydrogels exhibited transcriptional profiles that more closely resembled xenograft tumors than conventional 2D monolayers. Pathway-level analysis and regression-based benchmarking revealed restoration of critical hallmark programs, including proliferation, immune signaling, developmental pathways, and stress response cascades. While the 3D model does not fully recapitulate the complexity of the tumor microenvironment, its chemically defined, tunable, and reproducible design offers an accessible, physiologically informative model of lung adenocarcinoma that restores key transcriptional and functional features lost in conventional culture systems.