Transcriptional changes consistent with impaired neuronal differentiation, angiogenesis, and tumor plasticity induced in human subpallial telencephalic organoid-glioblastoma chimeras

Abstract

Glioblastoma multiforme (GBM) is one of the most aggressive and therapy-resistant brain tumors prevalent in both adults and children. Despite extensive research to understand GBM pathology, it remains unclear how neural cells in the human brain interact with GBM cells to support their brain propagation and therapy resistance and whether GBM cells exert any influence on the properties of human neural cells. In this study, we co-culture human stem cell-derived subpallial telencephalic organoids with patient-derived proneural or mesenchymal GBM spheroids to investigate their reciprocal interactions. We show that both proneural and mesenchymal GBM spheroids readily fuse and propagate with human organoids, forming organoid-GBM chimeras, without the need for exogenous growth factors. GBM cells within the chimeras adapt by modulating gene expression profiles consistent with diminished proliferation, heightened hypoxia, increased angiogenesis, and proneural-to-mesenchymal transition in proneural GBM. Both proneural or mesenchymal GBMs also exert an impact on the properties of neural cells in the chimeras, leading to the suppression of neuronal genes and an upregulation expression of genes associated with hypoxia and angiogenesis. Collectively, this study identifies specific genes and molecular pathways that can be altered in GBM and neural cells by reciprocal interactions in a human developing brain-like environment for an increased understanding of GBM pathology and future therapy development.