Faculty, Staff and Student Publications
Publication Date
5-1-2025
Journal
Nature Genetics
DOI
10.1038/s41588-025-02167-5
PMID
40346361
PMCID
PMC12081307
PubMedCentral® Posted Date
5-9-2025
PubMedCentral® Full Text Version
Post-print
Abstract
In isocitrate dehydrogenase wildtype glioblastoma (GBM), cellular heterogeneity across and within tumors may drive therapeutic resistance. Here we analyzed 121 primary and recurrent GBM samples from 59 patients using single-nucleus RNA sequencing and bulk tumor DNA sequencing to characterize GBM transcriptional heterogeneity. First, GBMs can be classified by their broad cellular composition, encompassing malignant and nonmalignant cell types. Second, in each cell type we describe the diversity of cellular states and their pathway activation, particularly an expanded set of malignant cell states, including glial progenitor cell-like, neuronal-like and cilia-like. Third, the remaining variation between GBMs highlights three baseline gene expression programs. These three layers of heterogeneity are interrelated and partially associated with specific genetic aberrations, thereby defining three stereotypic GBM ecosystems. This work provides an unparalleled view of the multilayered transcriptional architecture of GBM. How this architecture evolves during disease progression is addressed in the companion manuscript by Spitzer et al.
Keywords
Humans, Glioblastoma, Brain Neoplasms, Gene Expression Regulation, Neoplastic, Isocitrate Dehydrogenase, Transcription, Genetic, Transcriptome, Gene Expression Profiling
Published Open-Access
yes
Recommended Citation
Nomura, Masashi; Spitzer, Avishay; Johnson, Kevin C; et al., "The Multilayered Transcriptional Architecture of Glioblastoma Ecosystems" (2025). Faculty, Staff and Student Publications. 4520.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4520
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