Title
Transcriptome analysis reveals tumor microenvironment changes in glioblastoma
Author
Hoogstrate, Youri (Erasmus MC)
Draaisma, Kaspar (University Medical Center Utrecht)
Barin, N. (TU Delft Micro and Nano Engineering; Erasmus MC)
Taphoorn, Martin J.B. (Haaglanden Medical Center; Leiden University Medical Center)
Weyerbrock, Astrid (University of Freiburg)
Sanson, Marc (Sorbonne Université)
Hoeben, Ann (Maastricht UMC)
Lukacova, Slávka (Århus University Hospital)
Lombardi, Giuseppe (Veneto Institute of Oncology IOV-IRCCS)
Hanse, Monique (Catharina Hospital)
Fleischeuer, Ruth E.M. (Elisabeth-TweeSteden Hospital)
Watts, Colin (University of Birmingham, College of Medical and Dental Sciences)
Angelopoulos, Nicos (Cardiff University)
Gorlia, Thierry (EORTC Headquarters)
Robe, Pierre A. (University Medical Center Utrecht; Universite de Liege)
French, P.J. (Erasmus MC)
Date
2023
Abstract
A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.
Subject
extracellular matrix
glioblastoma
neurons
pericytes
recursive correlation
RNA-seq
single-nucleus RNA-seq
tumor evolution
To reference this document use:
http://resolver.tudelft.nl/uuid:e1dac829-d976-4cc2-bf8b-ec5e0c05ed5e
DOI
https://doi.org/10.1016/j.ccell.2023.02.019
ISSN
1535-6108
Source
Cancer Cell, 41 (4), 678-692.e7
Part of collection
Institutional Repository
Document type
journal article
Rights
© 2023 Youri Hoogstrate, Kaspar Draaisma, N. Barin, Martin J.B. Taphoorn, Astrid Weyerbrock, Marc Sanson, Ann Hoeben, Slávka Lukacova, Giuseppe Lombardi, Monique Hanse, Ruth E.M. Fleischeuer, Colin Watts, Nicos Angelopoulos, Thierry Gorlia, Pierre A. Robe, P.J. French