Microenvironment-driven dynamic chromatin changes in glioblastoma recapitulate early neural development at single-cell resolution

While the tumor microenvironment is necessary for recapitulating the intratumoral heterogeneity and cell state plasticity found in human primary glioblastomas (GBM), the underlying transcriptional regulation of these states remains unknown. Using our Glioblastoma Cerebral Organoid (GLICO) model, we profiled the chromatin accessibility of 28,040 single cells in five patient-derived glioma stem cell lines. By integrating matched transcriptomes, we define the chromatin states and transcriptional regulators mediating GBM cellular state diversity including DLX5/6 in the neural progenitor-like state, ASCL1 in the oligodendrocyte progenitor-like state, RUNX1 in the astrocyte-like state and FOSL1/2 in the mesenchymal-like state. Despite large differences between tumors, we find a shared cellular compartment made up of neural progenitor-like cells and radial glia-like cells, whose dynamic changes in chromatin accessibility are reminiscent of early neural development. Together, our results shed light on the transcriptional regulation program in GBM and define novel early developmental cell states.