Integrated single cell spatial multi-omics landscape of WHO grades 2-4 diffuse gliomas identifies locoregional metabolomic regulators of glioma growth

作者：Yanxia Ma, Shamini Ayyadhury, Sanjay K. Singh, Yashu Vashishath, Cagri Ozdemir, Trevor D. McKee, N. Rich Nguyen, Akshay Basi, Duncan H. Mak, Javier A. Gomez, Jason T. Huse, Sana Noor, Dan Winkowski, Regan Baird, Jeffrey S. Weinberg, Frederick F. Lang, Jared K. Burks, Serdar Bozdag, Erin H. Seeley, Chibawanye Ene · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.04.30.651361 · 被引用次数：3 · 研究领域：Glioma Diagnosis and Treatment、Single-cell and spatial transcriptomics、Radiomics and Machine Learning in Medical Imaging

Abstract Diffuse infiltrating gliomas are aggressive tumors of the central nervous system driven by intra-tumoral heterogeneity and aberrant normal-tumor cell-cell interactions. Grade specific and locoregional metabolic dependencies driving aberrant cell-states linked to treatment resistance, seizures and infiltration of gliomas remain elusive. Here, we applied spatial transcriptomics (stRNAseq), imaging mass cytometry (IMC) and mass spectrometry imaging (MSI; metabolites, peptides and glycans) to the core and edge tumor tissue from patients with World Health Organization (WHO) grades 2-4 diffuse infiltrating gliomas including isocitrate dehydrogenase (IDH) mutant oligodendrogliomas (WHO Grades 2 and 3) and IDH wildtype astrocytomas including ‘anaplastic’ astrocytoma (prior 2016 WHO histological grade 3) and glioblastoma (GBM, WHO grade 4) stRNAseq identified regions-specific differentially expressed genes with significant overall survival implications particularly in IDH wildtype GBM. Integration of stRNA seq and MSI-derived metabolite expression demonstrated enrichment of L-glutamine in SOX4 + Neural progenitor-like (NPC-like) cells and DL-dopamine in GPNMB + Mesenchymal-like (MES-like) GBM cells at the tumor edge relative to the core. Our results uncover clinically relevant and locoregional cell state-specific metabolites that may contribute to GBM proliferation, infiltration and seizures. This comprehensive pan-diffuse infiltrating glioma multi-omics study could serve as ...