Blood-tumor Barrier Organoids Recapitulate Glioblastoma Microenvironment and Enable High-Throughput Modeling of Therapeutic Delivery

The blood-brain barrier (BBB) is a highly specialized system that is critical for regulating transport between the blood and the central nervous system. In brain tumors, the vasculature system is compromised, and is referred to as the blood-tumor barrier (BTB). The ability to precisely model the unique physiological properties of the BTB is essential to decipher its role in tumor pathophysiology and for the rational design of efficacious therapeutics. Here, we introduce a robust and high-throughput in vitro 3D human BTB organoid model that recapitulates various key features of the BTB observed in vivo and in clinical GBM samples. The organoids are composed of patient-derived glioblastoma stem cells (GSCs), human brain endothelial cells (EC), astrocytes and pericytes, which are formed through self-assembly. Transcriptomic and functional analyses reveal that the GSCs in the BTB organoids exhibit enhanced level of stemness, mesenchymal signature, invasiveness and angiogenesis, and this is further confirmed in in vivo studies. We demonstrate the ability of the BTB organoids to model therapeutic delivery and drug efficacy on brain tumor cells. Collectively, our findings show that the BTB organoid model has broad utility as a clinically representative system for studying the BTB and evaluating brain tumor therapies. ### Competing Interest Statement The authors have declared no competing interest.