Collagen/fibronectin-based lung carcinoma culture platform: development and characterization of a new tumor model for vascular mimicry study

Lung cancer is a prevalent and deadly malignancy worldwide. Traditional angiogenesis has been augmented by the discovery of vascular mimicry (VM), an alternative mechanism where tumor cells form vascular-like structures that contribute to tumor aggressiveness independent of endothelial vessels. The study of VM has been constrained by limitations in existing <i>in vitro</i> models, particularly conventional tissue culture-treated plates, which fail to fully replicate the complex tumor microenvironment. Existing biomimetic models are yet to effectively reproduce VM signatures specific to non-small cell lung cancer (NSCLC), hindering further research and therapeutic development. In this context, our research aimed to address these challenges by exploring collagen/fibronectin biological macromolecules as novel biomimetic environments to study VM in NSCLC. Here, we created a collagen/fibronectin-based engineered tumor model both <i>in vivo</i> and <i>in vitro</i> to explore how these matrices affect cellular behaviors, including proliferation, colony formation, migration, stemness, and VM formation. Using extensive gene expression profiling, we characterized NSCLC cells grown in these matrices to identify key genes influencing VM formation. Furthermore, we selected two reported anti-tumor drugs and their potential VM inhibitory effects and verified the practical application of this model by developing a VM-rich tumor model <i>in vivo</i>. Our findings underscore the pivotal role of ECM components, particularly collagen and fibronectin, in modulating critical biological processes in cancer and VM formation. In addition, the two antitumor agents we selected have the potential to inhibit VM occurrence. By simulating the ECM environment conducive to VM, we developed a VM-rich tumor model, and our study provided insights into potential mechanisms underlying VM formation and its regulation in NSCLC.