Spatial Transcriptomics of Glioblastoma Defines Spatially Anchored Transcriptional Activity Informing Therapeutic Vulnerability and Resistance

Abstract

Intratumoral heterogeneity is thought to hinder targeted therapy in glioblastoma (GBM), but the extent of variation in known targets and tumor cell-intrinsic and extrinsic regulatory mechanisms within tissue remains unclear. In this work, we use Visium spatial transcriptomics to profile 44 tumor slides and 128,176 niche-annotated ST spots, including 14 new slides from 7 GBM specimens, along with spatial annotation from the Ivy Glioblastoma Atlas Project. First, we characterize the differential expression of AVB3, EGFR, VEGF, and PDGFRA pathway activities across space, elucidating the limited success of individual targeted therapies. Second, we identify transcription factor modules driving intratumoral heterogeneity and characterize a novel transcription factor module at the interface between core tumor and the invasive edge. Third, we identify cell type-specific receptor-ligand signaling enriched in specific spatial niches and relate these to specific molecular program alterations. Finally, we identify and characterize transcriptional pathways and their activity across spatial niches through transcription network analysis and demonstrate how these pathways can inform a combined therapeutic approach. Together, through novel insights into the spatial patterning of transcription factor regulation, cellular interactions, and biological pathway activity, our work informs rational combination therapies targeting spatial niche specific vulnerabilities.