Transcriptome analysis reveals tumor microenvironment changes in glioblastoma

Youri Hoogstrate; Kaspar Draaisma; Santoesha A. Ghisai; Levi van Hijfte; Nastaran Barin; Iris de Heer; Wouter Coppieters; Thierry P.P. van den Bosch; Anne Bolleboom; Zhenyu Gao; Arnaud J.P.E. Vincent; Latifa Karim; Manon Deckers; Martin J.B. Taphoorn; Melissa Kerkhof; Astrid Weyerbrock; Marc Sanson; Ann Hoeben; Slávka Lukacova; Giuseppe Lombardi; Sieger Leenstra; Monique Hanse; Ruth E.M. Fleischeuer; Colin Watts; Nicos Angelopoulos; Thierry Gorlia; Vassilis Golfinopoulos; Vincent Bours; Martin J. van den Bent; Pierre A. Robe; Pim J. French

doi:10.1016/j.ccell.2023.02.019

Transcriptome analysis reveals tumor microenvironment changes in glioblastoma

Youri Hoogstrate^*
, Kaspar Draaisma
, Santoesha A. Ghisai
, Levi van Hijfte
, Nastaran Barin
, Iris de Heer
, Wouter Coppieters
, Thierry P.P. van den Bosch
, Anne Bolleboom
, Zhenyu Gao
, Arnaud J.P.E. Vincent
, Latifa Karim
, Manon Deckers
, Martin J.B. Taphoorn
, Melissa Kerkhof
, Astrid Weyerbrock
, Marc Sanson
, Ann Hoeben
, Slávka Lukacova
, Giuseppe Lombardi

Sieger Leenstra, Monique Hanse, Ruth E.M. Fleischeuer, Colin Watts, Nicos Angelopoulos, Thierry Gorlia, Vassilis Golfinopoulos, Vincent Bours, Martin J. van den Bent, Pierre A. Robe, Pim J. French^*

^*Corresponding author for this work

University of Liege
Haaglanden Medisch Centrum
Leiden University Medical Centre
University of Freiburg Medical Center
University of Freiburg
Hôpital La Pitié-Salpêtrière
Maastricht University Medical Centre
Aarhus University Hospital
IRCCS Istituto Oncologico Veneto - Padova
Catharina Hospital
ETZ Elisabeth
University of Birmingham, College of Medical and Dental Sciences
Cardiff University
European Organisation for Research and Treatment of Cancer Data Center
Utrecht University
Erasmus University Rotterdam

Research output: Contribution to journal › Article › Academic › peer-review

155 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	678-692.e7
Journal	Cancer Cell
Volume	41
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2023.02.019
Publication status	Published - 10 Apr 2023

Bibliographical note

Acknowledgments:
This project has been funded by De Westlandse Ride and The Brain Tumour Charity grant number ET_2019/2_10470 and Télévie grant number 7.6514.17 from Belgium. N.A. is supported by the Ser Cymru II program, which is partly funded by Cardiff University and the European Regional Development Fund through the Welsh Government . The graphical abstract was made using BioRender.com .

Publisher Copyright:
© 2023 The Authors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Cite this

Hoogstrate, Y., Draaisma, K., Ghisai, S. A., van Hijfte, L., Barin, N., de Heer, I., Coppieters, W., van den Bosch, T. P. P., Bolleboom, A., Gao, Z., Vincent, A. J. P. E., Karim, L., Deckers, M., Taphoorn, M. J. B., Kerkhof, M., Weyerbrock, A., Sanson, M., Hoeben, A., Lukacova, S., ... French, P. J. (2023). Transcriptome analysis reveals tumor microenvironment changes in glioblastoma. Cancer Cell, 41(4), 678-692.e7. https://doi.org/10.1016/j.ccell.2023.02.019

@article{3a463561d5d74c0194850e8b3c59d865,

title = "Transcriptome analysis reveals tumor microenvironment changes in glioblastoma",

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.",

author = "Youri Hoogstrate and Kaspar Draaisma and Ghisai, \{Santoesha A.\} and \{van Hijfte\}, Levi and Nastaran Barin and \{de Heer\}, Iris and Wouter Coppieters and \{van den Bosch\}, \{Thierry P.P.\} and Anne Bolleboom and Zhenyu Gao and Vincent, \{Arnaud J.P.E.\} and Latifa Karim and Manon Deckers and Taphoorn, \{Martin J.B.\} and Melissa Kerkhof and Astrid Weyerbrock and Marc Sanson and Ann Hoeben and Sl{\'a}vka Lukacova and Giuseppe Lombardi and Sieger Leenstra and Monique Hanse and Fleischeuer, \{Ruth E.M.\} and Colin Watts and Nicos Angelopoulos and Thierry Gorlia and Vassilis Golfinopoulos and Vincent Bours and \{van den Bent\}, \{Martin J.\} and Robe, \{Pierre A.\} and French, \{Pim J.\}",

note = "Acknowledgments: This project has been funded by De Westlandse Ride and The Brain Tumour Charity grant number ET\_2019/2\_10470 and T{\'e}l{\'e}vie grant number 7.6514.17 from Belgium. N.A. is supported by the Ser Cymru II program, which is partly funded by Cardiff University and the European Regional Development Fund through the Welsh Government . The graphical abstract was made using BioRender.com . Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = apr,

day = "10",

doi = "10.1016/j.ccell.2023.02.019",

language = "English",

volume = "41",

pages = "678--692.e7",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

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Hoogstrate, Y, Draaisma, K, Ghisai, SA , van Hijfte, L , Barin, N, de Heer, I, Coppieters, W, van den Bosch, TPP , Bolleboom, A , Gao, Z , Vincent, AJPE, Karim, L, Deckers, M, Taphoorn, MJB, Kerkhof, M, Weyerbrock, A, Sanson, M, Hoeben, A, Lukacova, S, Lombardi, G, Leenstra, S, Hanse, M, Fleischeuer, REM, Watts, C, Angelopoulos, N, Gorlia, T, Golfinopoulos, V, Bours, V, van den Bent, MJ, Robe, PA & French, PJ 2023, 'Transcriptome analysis reveals tumor microenvironment changes in glioblastoma', Cancer Cell, vol. 41, no. 4, pp. 678-692.e7. https://doi.org/10.1016/j.ccell.2023.02.019

TY - JOUR

T1 - Transcriptome analysis reveals tumor microenvironment changes in glioblastoma

AU - Hoogstrate, Youri

AU - Draaisma, Kaspar

AU - Ghisai, Santoesha A.

AU - van Hijfte, Levi

AU - Barin, Nastaran

AU - de Heer, Iris

AU - Coppieters, Wouter

AU - van den Bosch, Thierry P.P.

AU - Bolleboom, Anne

AU - Gao, Zhenyu

AU - Vincent, Arnaud J.P.E.

AU - Karim, Latifa

AU - Deckers, Manon

AU - Taphoorn, Martin J.B.

AU - Kerkhof, Melissa

AU - Weyerbrock, Astrid

AU - Sanson, Marc

AU - Hoeben, Ann

AU - Lukacova, Slávka

AU - Lombardi, Giuseppe

AU - Leenstra, Sieger

AU - Hanse, Monique

AU - Fleischeuer, Ruth E.M.

AU - Watts, Colin

AU - Angelopoulos, Nicos

AU - Gorlia, Thierry

AU - Golfinopoulos, Vassilis

AU - Bours, Vincent

AU - van den Bent, Martin J.

AU - Robe, Pierre A.

AU - French, Pim J.

N1 - Acknowledgments: This project has been funded by De Westlandse Ride and The Brain Tumour Charity grant number ET_2019/2_10470 and Télévie grant number 7.6514.17 from Belgium. N.A. is supported by the Ser Cymru II program, which is partly funded by Cardiff University and the European Regional Development Fund through the Welsh Government . The graphical abstract was made using BioRender.com . Publisher Copyright: © 2023 The Authors

PY - 2023/4/10

Y1 - 2023/4/10

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85151026018

U2 - 10.1016/j.ccell.2023.02.019

DO - 10.1016/j.ccell.2023.02.019

M3 - Article

C2 - 36898379

AN - SCOPUS:85151026018

SN - 1535-6108

VL - 41

SP - 678-692.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

Transcriptome analysis reveals tumor microenvironment changes in glioblastoma

Abstract

Bibliographical note

UN SDGs

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