The Multi-Layered Transcriptional Architecture of Glioblastoma Ecosystems [10X]

To comprehensively define the cellular heterogeneity of glioblastoma (GBM), the GBM CARE (Cellular Analysis of Resistance and Evolution) consortium set out to profile 121 GBMs with extensive clinical annotation, by single-nucleus RNA-sequencing and bulk tumor DNA sequencing. The resulting dataset enabled us to characterize GBM heterogeneity at three levels. First, GBMs are classified by their cellular composition, encompassing malignant, immune, neuronal and glial cell types. Second, within each cell type, and particularly among the malignant cells, we describe the diversity of cellular states and their pathway-based functional activities. Third, after controlling for the frequencies of cellular states, we find that the remaining variation between GBMs highlights three baseline gene expression programs which we labeled Neuronal, Glial, and Extracellular Matrix. These three layers of heterogeneity are inter-related and partially associated with specific genetic aberrations, thereby defining three stereotypic ecosystems in GBM. This work provides an unparalleled view of the multi-layered transcriptional architecture of GBM.