Abstract

Metastasis is the leading cause of mortality in non-small cell lung cancer (NSCLC). Accurate assessment of the anti-metastasis effects is critical for developing anti-NSCLC agents. However, existing preclinical models failed to recapitulate and precisely quantify key events during tumor metastasis, including alternative vascularization, hampering mechanistic studies and the discovery of efficacious anti-metastasis agents for NSCLC therapy. Here, we developed a Vascularized Lung Tumoroid-on-a-Chip (VLTOC) platform that precisely reconstitutes the critical tumor-vasculature interface and dynamically recapitulates mosaic vessel (MV) formation, a key intermediate in NSCLC metastasis. Compared to conventional spheroid models, the genes associated with tumor proliferation, metabolism, and invasion were significant upregulated in VLTOC. Notably, VLTOC dynamically recapitulated MV formation at single-cell resolution, enabling the development of quantitative metrics for anti-NSCLC drug testing based on tumoroid expansion and MV development. Validation with five standard chemotherapeutics revealed high concordance with clinical drug sensitivity data. Furthermore, the VLTOC platform showed high concordance with a xenograft mouse model in assessing the pharmacological and toxicological profile of rocaglamide. Collectively, the VLTOC platform and its associated quantitative metrics provide a powerful tool for the simultaneous assessment of anti-tumor efficacy, thereby facilitating mechanistic studies of NSCLC metastasis and accelerating the discovery of novel therapeutics.