Tumor Microenvironment Is Critical for the Maintenance of Cellular States Found in Primary Glioblastomas

TLDR

Glioblastoma is an incurable, highly heterogeneous tumor whose cellular plasticity makes it difficult to model, and it remains unclear how well current patient‑derived models recapitulate the full heterogeneity of primary tumors. The study aims to provide a complete transcriptomic characterization of major patient‑derived GBM model types by comparing single‑cell RNA sequencing data from five patients across four GSC‑derived models. Researchers performed single‑cell RNA sequencing of tumor cells from five patients across glioma spheres, tumor organoids, glioblastoma cerebral organoids (GLICO), and patient‑derived xenografts. The GLICO model, which incorporates a neuroanatomically accurate human microenvironment, recapitulates the neural progenitor‑like subpopulation and cellular plasticity of primary tumors, demonstrating that the microenvironment is critical and sufficient for maintaining GSC cellular states. Commentary by Luo and Weiss (p.907) and an In This Issue feature.

Abstract

Abstract Glioblastoma (GBM), an incurable tumor, remains difficult to model and more importantly to treat due to its genetic/epigenetic heterogeneity and plasticity across cellular states. The ability of current tumor models to recapitulate the cellular states found in primary tumors remains unexplored. To address this issue, we compared single-cell RNA sequencing of tumor cells from 5 patients across four patient-specific glioblastoma stem cell (GSC)–derived model types, including glioma spheres, tumor organoids, glioblastoma cerebral organoids (GLICO), and patient-derived xenografts. We find that GSCs within the GLICO model are enriched for a neural progenitor–like cell subpopulation and recapitulate the cellular states and their plasticity found in the corresponding primary parental tumors. These data demonstrate how the contribution of a neuroanatomically accurate human microenvironment is critical and sufficient for recapitulating the cellular states found in human primary GBMs, a principle that may likely apply to other tumor models. Significance: It has been unclear how well different patient-derived GBM models are able to recreate the full heterogeneity of primary tumors. Here, we provide a complete transcriptomic characterization of the major model types. We show that the microenvironment is crucial for recapitulating GSC cellular states, highlighting the importance of tumor–host cell interactions. See related commentary by Luo and Weiss, p. 907. This article is highlighted in the In This Issue feature, p. 890