UCLA researchers have developed new 3D tumor organoid models that allow for detailed study of glioblastoma, an aggressive brain cancer. These models, created from human stem cells, closely mimic the environment of the human brain and provide insight into how glioblastoma interacts with surrounding brain tissue and the immune system.
The research, published in Cell Reports, introduces two complementary organoid systems. The first, called the Human Organoid Tumor Transplantation (HOTT) system, enables scientists to observe how glioblastoma communicates with nearby brain cells. Using this model, researchers identified PTPRZ1—a protein found in both tumor and adjacent brain cells—as a key regulator of tumor behavior.
When PTPRZ1 levels were reduced specifically in the non-cancerous brain cells within the organoids, tumor cells became more aggressive and invasive. They activated genes associated with movement and tissue invasion and formed longer cellular extensions known as tumor microtubes. Notably, these changes did not depend on PTPRZ1’s usual enzyme activity but rather on its role as a signaling mediator.
"This study shows that glioblastoma is strongly influenced by the surrounding brain cells, not just the cancer itself," said Bhaduri, who is also a member of the UCLA Broad Stem Cell Research Center. "By identifying PTPRZ1 as a new regulator of tumor behavior, we're revealing hidden communication pathways and demonstrating how these organoid models can help uncover more effective therapeutic targets."
The second model developed by UCLA scientists is called immune-human organoid tumor transplantation (iHOTT). This builds upon HOTT by adding immune system components to better replicate how glioblastoma responds to immunotherapy treatments.
The iHOTT model maintains important features of both tumors and immune cells—including CD4 and CD8 T cells, B cells, NK cells, and myeloid cells—allowing for observation of cell-to-cell communication and responses to therapy. Researchers tested pembrolizumab—a PD-1 checkpoint inhibitor—on these organoids. While treatment increased activation of certain immune cell types such as CD4 T cells and B cells, it did not stop tumor growth.
"These immune changes observed in the lab closely mirrored what happens in real patients treated with pembrolizumab," said Bhaduri. "The same shifts in immune cell populations occurred, the same communication pathways between immune cells were activated, and even rare or unconventional immune cell types expanded in similar ways. This demonstrates that iHOTT faithfully reproduces patient-like immune responses in a human-relevant system."
Further analysis showed that pembrolizumab increased T cell diversity; however, each patient's response was unique due to individual differences in T cell receptors. Most notably, expansion was seen among CD4 T cells with characteristics linked to sustained immunity. These results help explain why PD-1 inhibitors have limited effectiveness against glioblastoma: few T cells target shared features across different patients’ tumors.
Researchers say these findings highlight how advanced organoid models can reveal mechanisms missed by traditional animal studies or standard laboratory cultures.
"Together, these studies show that these patient-specific organoid models offer a powerful tool to uncover hidden tumor interactions and test new therapies, bringing personalized treatment for this deadly cancer a step closer," said Bhaduri.
