UCLA Scientists Pioneer Advanced 3D Organoid Models for Glioblastoma Research
UCLA scientists have developed advanced miniature 3D tumor organoid models to study glioblastoma, an aggressive brain cancer. These models aim to provide a setting that closely mirrors the human brain, allowing researchers to understand how the cancer interacts with surrounding brain cells and the immune system. This interaction significantly contributes to the cancer's invasiveness and resistance to therapy.
Detailed in two studies published in Cell Reports, these innovative organoid models are constructed from human stem cells and incorporate various cell types found in the human brain. This methodology enables direct observation of communication between patient-derived tumors and healthy brain tissue, potentially identifying vulnerabilities for personalized therapies.
Aparna Bhaduri, PhD, a senior author of the studies and assistant professor at UCLA, stated that these models are crucial for understanding how interactions with brain tissue and immune cells contribute to therapy failure, facilitating the development of more effective treatments.
Human Organoid Tumor Transplantation (HOTT) System
The first model, named the HOTT system, investigates how glioblastoma communicates with surrounding brain cells. This communication can lead to changes in tumor identity, tissue invasion, and treatment resistance.
Researchers identified PTPRZ1, a protein expressed by both tumor and nearby brain cells, as a key regulator of tumor behavior. When PTPRZ1 levels were reduced in the brain cells of the organoids, tumor cells shifted to a more aggressive, invasive state, activating genes linked to movement and invasion. They also formed longer tumor microtubes, which aid tumor spread and treatment resistance. These effects occurred without directly altering tumor cell PTPRZ1, suggesting a previously unrecognized role for the protein as a signaling mediator.
Immune-Human Organoid Tumor Transplantation (iHOTT) Model
The second model, the iHOTT model, enhances the HOTT system by integrating immune system components into the organoids. This allows scientists to study how immune cells influence tumor growth and therapy resistance, simulating glioblastoma's response to immunotherapy.
The iHOTT model preserves critical features of both tumor and immune cells, including various T cells, B cells, NK cells, and myeloid cells. This enables observation of cellular communication, immune cell behavior, and population changes in response to the tumor.
When organoids were treated with pembrolizumab, a PD-1 checkpoint inhibitor, the drug activated the immune system, increasing CD4 T cells, B cells, and immune signaling. However, tumor cells continued to survive and grow. This indicated that while pembrolizumab can activate the immune system, it is insufficient to destroy glioblastoma on its own.
Immune changes observed in the lab, such as shifts in immune cell populations and activated communication pathways, closely resembled responses in glioblastoma patients treated with pembrolizumab. T cell receptor sequencing showed that pembrolizumab increased T cell diversity, but these new T cells were unique to individual organoids. The most significant expansion occurred in CD4 T cells with a "stem-like" profile. These findings suggest why PD-1 inhibitors have limited benefit in glioblastoma, as patient immune responses vary, and few T cells target shared tumor components.
These organoid models are considered powerful tools for uncovering hidden tumor interactions and testing new therapies, moving closer to personalized treatments for glioblastoma.