Modeling Patient-Derived Glioblastoma with Cerebral Organoids

TLDR

Glioblastoma has a dismal prognosis with a median survival of about 15 months, and current preclinical models lack a normal human microenvironment and fail to recapitulate GBM biology. The study aims to create a patient‑specific GBM model by combining patient‑derived glioma stem cells with human embryonic stem cell–derived cerebral organoids. The model retro‑engineers GBMs by integrating GSCs into hESC‑derived cerebral organoids, allowing tumor growth within a human‑like microenvironment. The GLICO model demonstrates that GSCs home to, invade, and proliferate within organoids, forming tumors that closely phenocopy patient GBMs, rapidly develop, and are supported by tumor microtubes that aid invasion of host tissue, providing a platform for ex vivo modeling and high‑throughput drug screening.

Abstract

The prognosis of patients with glioblastoma (GBM) remains dismal, with a median survival of approximately 15 months. Current preclinical GBM models are limited by the lack of a "normal" human microenvironment and the inability of many tumor cell lines to accurately reproduce GBM biology. To address these limitations, we have established a model system whereby we can retro-engineer patient-specific GBMs using patient-derived glioma stem cells (GSCs) and human embryonic stem cell (hESC)-derived cerebral organoids. Our cerebral organoid glioma (GLICO) model shows that GSCs home toward the human cerebral organoid and deeply invade and proliferate within the host tissue, forming tumors that closely phenocopy patient GBMs. Furthermore, cerebral organoid tumors form rapidly and are supported by an interconnected network of tumor microtubes that aids in the invasion of normal host tissue. Our GLICO model provides a system for modeling primary human GBM ex vivo and for high-throughput drug screening.