A vascularized tumors-on-a-chip model for studying tumor-angiogenesis interplay, heterogeneity and drug responses
Suyeon Shin, Yurim Choi, Won-Jun Jang, Batjargal Ulziituya, Giheon Ha, Raehui Kang, Soojin Park, Min‐Seok Kim, Yu Shrike Zhang, Hanjun Kim, Junmin Lee
Abstract
Current tumor models struggle to replicate the complexity of the tumor microenvironment, particularly endothelial sprouting and vascular-tumor interactions. To address these limitations, we developed a vascularized tumors-on-a-chip model by fusing tumor spheroids with HUVEC spheroids to simulate angiogenesis. The model incorporates hypoxia-driven cytokine secretion and dynamic endothelial penetration, enabling accurate recapitulation of angiogenic processes. Spheroids were optimized for size and viability, and four cancer types were studied, with GBM and A549 exhibiting the highest angiogenic potential, as confirmed by Z-stack imaging and qRT-PCR. Encapsulation in GelMA and integration into PDMS-based microfluidic chips provided a dynamic flow environment, mimicking in vivo drug delivery while enabling high-throughput drug screening. This chip-based system allows simultaneous testing of multiple drugs or tumors under physiologically relevant conditions, enhancing its translational potential. The platform was validated using doxorubicin and bevacizumab, revealing reduced VEGF secretion and dynamic cytokine responses, replicating vascular barriers. Further validation in murine models demonstrated its capacity to promote angiogenesis and mimic tumor-vessel interactions. This advanced tumors-on-a-chip model addresses critical shortcomings of conventional 2D and 3D systems and offers a transformative tool for preclinical drug evaluation and the development of precision oncology strategies, bridging the gap between in vitro testing and in vivo relevance. • A biomaterial-based vascularized tumor model using spheroid fusion (tumor and HUVEC spheroids) can replicate in vivo tumor angiogenesis. • By incorporating engineered biomaterials, the model enhances the structural and functional fidelity of tumor-vascular interactions. • Angiogenic differences among tumors from various organs are analyzed, and the model is integrated into a fluidic device for drug testing. • A biomaterial-supported fluidic drug screening platform is also established to evaluate anti-angiogenic cancer treatments, highlighting the role of biomaterials in tumor microenvironment engineering. • Biomaterial-supported platforms advance tumor microenvironment modeling and screening of angiogenesis-targeted drugs.