Transcriptome analysis reveals tumor microenvironment changes in glioblastoma

Hoogstrate, Youri, Draaisma, Kaspar, Ghisai, Santoesha A., van Hijfte, Levi, Barin, Nastaran, de Heer, Iris, Coppieters, Wouter, van den Bosch, Thierry P.P., Bolleboom, Anne, Gao, Zhenyu, Vincent, Arnaud J.P.E., Karim, Latifa, Deckers, Manon, Taphoorn, Martin J.B., Kerkhof, Melissa, Weyerbrock, Astrid, Sanson, Marc, Hoeben, Ann, Lukacova, Slávka, Lombardi, Giuseppe, Leenstra, Sieger, Hanse, Monique, Fleischeuer, Ruth E.M., Watts, Colin, Angelopoulos, Nicos ORCID: https://orcid.org/0000-0002-7507-9177, Gorlia, Thierry, Golfinopoulos, Vassilis, Bours, Vincent, van den Bent, Martin J., Robe, Pierre A. and French, Pim J. 2023. Transcriptome analysis reveals tumor microenvironment changes in glioblastoma. Cancer Cell 41 (4) , pp. 678-692. 10.1016/j.ccell.2023.02.019

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Cell Press
ISSN:	1535-6108
Date of First Compliant Deposit:	22 March 2023
Date of Acceptance:	14 February 2023
Last Modified:	11 Nov 2023 19:11
URI:	https://orca.cardiff.ac.uk/id/eprint/157878

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