Spatial Multiomics Defines a Shared Tumor Infiltrative Signature at the Resection Margin in High-Grade Gliomas

作者：Balagopal Pai, Susana Isabel Ramos, Wan Sze Cheng, Tanvi Joshi, Emine Özen, Lakshmi Shree Kulumani Mahadevan, Thenzing J. Silva-Hurtado, Gabrielle A. Price, Jessica Tomé-García, German Nudelman, Sanjana Shroff, Kristin G. Beaumont, Raymund L.M. Yong, Robert Sebra, Elena Zaslavsky, Nadejda M. Tsankova · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/0008-5472.can-24-4708 · 被引用次数：13 · 研究领域：Glioma Diagnosis and Treatment、Single-cell and spatial transcriptomics、Cancer Genomics and Diagnostics

Despite genomic heterogeneity, most high-grade gliomas (HGG), including IDH wild-type glioblastoma, display diffusely infiltrative growth, which impedes complete surgical resection and leads to inevitable recurrence. Understanding of HGG biology comes predominantly from studies using resected "core" tissue. Paradoxically, chemoradiation targets residual disease at the resection margin, which remains poorly defined. To address this, we generated a high-throughput single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) multiomic dataset from matching "core" and "margin" dissections in four distinct grade 4 HGG (36,811 snRNA-seq and 30,705 snATAC-seq nuclei after filtering from EGFR amplified, NF1 mutant, FGFR3-TACC3 fused, and IDH1 mutant HGG) and combined it with new spatial transcriptomics data from two additional HGG (EGFR amplified and CDK4 amplifed) to evaluate "core-to-margin" transition. Computational analyses included functional enrichment, comparison with prior HGG datasets, differential analyses in core versus margin cell types or regions of interest for genes, chromatin accessibility peaks, cell-cell interactions, transcription factor motif activity and associated regulon targets, and reconstruction of core-to-margin transition using RNA velocity and pseudotime. Contrasting tumor-specific biology in matching core and margin dissections defined a unique, shared "glioma infiltration" signatur...