A Zebrafish-Based Orthotopic Glioblastoma Xenograft Model for Preclinical Drug Screening and Clinical Drug Sensitivity Prediction

A reliable animal model that can mimic the GBM intracranial infiltration and Blood-brain barrier (BBB) interaction is necessary for effective therapeutics development. Here, we report a zebrafish-based orthotopic GBM xenograft model, in which GBM cells from different species and even patients, can robustly propagate and faithfully reproduce their histological characteristics. Single-cell RNA-seq indicates a transcriptomic adaption of GBM xenografts to infiltrative phenotype within the zebrafish brains. We also provide evidence that the BBB in zebrafish larva is molecularly and functionally intact and can interact with GBM cells in similar ways as in mammals, which together enables this model to accurately identify BBB penetrating drugs. Using GBM patients’ samples, we further generate zebrafish patient-derived orthotopic xenografts (z-PDOX) and proof-of-concept experiments indicate the short-term temozolomide response in z-PDOX can predict the long-term prognosis of corresponding GBM patients. These together illustrate the value of zebrafish GBM model in drug discovery and precision medicine. 1.Single-cell RNA seq for endothelial cells of zebrafish 2.Single-cell RNA seq for GBM cells implanted in zebrafish brain