Faculty, Staff and Student Publications

Publication Date

5-1-2025

Journal

Nature Genetics

DOI

10.1038/s41588-025-02168-4

PMID

40346362

PMCID

PMC12081298

PubMedCentral® Posted Date

5-9-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Glioblastoma, Tumor Microenvironment, Single-Cell Analysis, Brain Neoplasms, Genomics, Isocitrate Dehydrogenase, Male, Longitudinal Studies, Female, Neoplasm Recurrence, Local, Middle Aged

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.