Integrative Single-Cell, Spatial, and Bulk Transcriptomics Characterizes an Outcome-Associated, Spatially Organized Mesenchymal Program in IDH-Mutant Glioma

Abstract

Simple Summary Gliomas are brain tumors that differ widely in how aggressively they behave and in how long patients survive. We asked whether reproducible patterns of gene activity could point to clinically important features of these tumors. By combining data from individual cells, whole-tumor samples, and intact tissue sections, we identified a mesenchymal gene-expression program linked to inflammation and tissue remodeling. In two independent patient groups, this program was consistently associated with higher tumor grade and shorter survival, and within tumor tissue it was clearly organized in space. It could also be separated from the low-oxygen response that often accompanies it. A second gene-expression program, by contrast, showed no consistent relationship with survival. These findings identify a reproducible molecular feature of glioma aggressiveness and provide a basis for better biological classification and for the future development of clinically useful tumor markers.