Human Organoid Models

To systematically model the genetic spectrum that are affected in human GBM, we use human iPSC-derived organoid to dissect the genetic heterogeneity in GBM. Using CRISPR/Cas9, we generated a spectrum of mutation combinations (Pten, Trp53, Cdkn2a, Cdkn2b, Nf1, Rb1, Egfr, Tert etc.), which are the most frequently mutated genes in human GBM, in human iPSCs. We could induce GBM organoid from these cells, the GBM organoid (LEGO: Laboratory Engineered Glioma Organoid) derived from these cells recapitulate key molecular features of human GBM (npj Precision Oncology, 2024). We are using LEGO models to dissect the interaction between genetic heterogeneity and functional heterogeneity in GBM. Tumor stromal cells like blood vessels and  tumor associated macrophages are being integrated into the advanced LEGO^2.0 model. Drug screen are also being conducted to build a genotype-based drug reference for personalized treatment of GBM. LEGO represents a major breakthrough allows modeling human glioblastoma with defined mutations. 

Tumor organoids are important tools for cancer research, but current models have drawbacks which limit their applications for predicting response to therapy. To overcome this, we developed a fast, efficient and complex culture system (IPTO: individualized patient tumor organoids) which accurately recapitulate the cellular and molecular pathology of human brain tumors and predict patient responses (Cell Stem Cell, 2025). Patient-derived tumor explants were cultured in induced pluripotent stem cell (iPSC)-derived cerebral organoids, thus enabling culture of a wide range of human tumors in the central nervous system (CNS), including adult, pediatric and metastatic brain cancers. Histopathological, genomic, epigenomic and scRNA-seq analyses demonstrated that IPTOs model recapitulates cellular heterogeneity and molecular features of original tumors. Crucially, we showed that the IPTO model predicts patient-specific drug responses, including resistance mechanisms, in a prospective patient cohort. Collectively, the IPTO model represents a major breakthrough in preclinical modeling of human cancers, which provides a path toward personalized cancer therapy. Currently, IPTOs are being tested for personalized therapy, target discovery/validation and T cell based therapies.