Document Type
Article
Publication Date
5-9-2025
Original Citation
Nomura M,
Spitzer A,
Johnson K,
Garofano L,
Nehar-Belaid D,
Galili Darnell N,
Greenwald A,
Bussema L,
Oh Y,
Varn F,
D'Angelo F,
Gritsch S,
Anderson K,
Migliozzi S,
Gonzalez Castro L,
ChowdhFury T,
Robine N,
Reeves C,
Park J,
Lipsa A,
Hertel F,
Golebiewska A,
Niclou S,
Nusrat L,
Kellet S,
Das S,
Moon H,
Paek S,
Bielle F,
Laurenge A,
Di Stefano A,
Mathon B,
Picca A,
Sanson M,
Tanaka S,
Saito N,
Ashley D,
Keir S,
Ligon K,
Huse J,
Yung W,
Lasorella A,
Verhaak R,
Iavarone A,
Suvà M,
Tirosh I.
The multilayered transcriptional architecture of glioblastoma ecosystems. Nat Genet. 2025;57(5):1155-67.
Keywords
JGM, SS1, Humans, Glioblastoma, Brain Neoplasms, Gene Expression Regulation, Neoplastic, Isocitrate Dehydrogenase, Transcription, Genetic, Transcriptome, Gene Expression Profiling
JAX Source
Nat Genet. 2025;57(5):1155-67.
ISSN
1546-1718
PMID
40346361
DOI
https://doi.org/10.1038/s41588-025-02167-5
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.