Document Type
Article
Publication Date
5-1-2025
Original Citation
Spitzer A,
Johnson K,
Nomura M,
Garofano L,
Nehar-Belaid D,
Darnell N,
Greenwald A,
Bussema L,
Oh Y,
Varn F,
D'Angelo F,
Gritsch S,
Anderson K,
Migliozzi S,
Gonzalez Castro L,
Chowdhury 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,
Iavarone A,
Verhaak R,
Tirosh I,
Suvà M.
Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics. Nat Genet. 2025;57(5):1168-78.
Keywords
JGM, SS1, Humans, Glioblastoma, Tumor Microenvironment, Single-Cell Analysis, Brain Neoplasms, Genomics, Isocitrate Dehydrogenase, Male, Longitudinal Studies, Female, Neoplasm Recurrence, Local, Middle Aged
JAX Source
Nat Genet. 2025;57(5):1168-78.
ISSN
1546-1718
PMID
40346362
DOI
https://doi.org/10.1038/s41588-025-02168-4
Abstract
The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there a consistent longitudinal trajectory across the cohort. Nevertheless, specific trajectories were enriched in subsets of patients. Changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem. Our study provides a blueprint of GBM's diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them.
Creative Commons License
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