Transcriptome analysis reveals tumor microenvironment changes in glioblastoma
Cancer Cell, vol. 41, pp. 678–692.e7
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.
Authors 31
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Youri Hoogstrate corresponding
Affiliation as printed
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands. Electronic address: y.hoogstrate@erasmusmc.nl
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Neurosurgery, UMC Utrecht, 3584CX Utrecht, the Netherlands
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Affiliation as printed
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands; Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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Erasmus MC · Delft University of Technology
Affiliation as printed
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands; Department of Precision and Microsystems Engineering, Delft University of Technology, 2628CD Delft, the Netherlands
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Department of Precision and Microsystems Engineering, Delft University of Technology, 2628CD Delft, the Netherlands
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Affiliation as printed
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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Affiliation as printed
Genomics Platform, GIGA Institute, Université de Liège, 4000 Liège, Belgium
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Affiliation as printed
Department of Pathology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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Affiliation as printed
Deparment of Neuroscience, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands; Department of Neurosurgery, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Deparment of Neuroscience, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
Department of Neurosurgery, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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Affiliation as printed
Deparment of Neuroscience, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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Affiliation as printed
Department of Neurosurgery, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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Affiliation as printed
Genomics Platform, GIGA Institute, Université de Liège, 4000 Liège, Belgium
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Affiliation as printed
Genomics Platform, GIGA Institute, Université de Liège, 4000 Liège, Belgium
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Leiden University Medical Center · Medisch Centrum Haaglanden · Stichting Haaglanden Medisch Centrum
Affiliation as printed
Department of Neurology, Haaglanden Medical Center, 2512VA The Hague, the Netherlands; Department of Neurology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
Department of Neurology, Haaglanden Medical Center, 2512VA The Hague, the Netherlands
Department of Neurology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
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Medisch Centrum Haaglanden · Stichting Haaglanden Medisch Centrum
Affiliation as printed
Department of Neurology, Haaglanden Medical Center, 2512VA The Hague, the Netherlands
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Neurosurgery, Medical Center - University of Freiburg, 79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany
Department of Neurosurgery, Medical Center – University of Freiburg, 79106 Freiburg, Germany
Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany
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Centre National de la Recherche Scientifique · Inserm · Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital · Institut du Cerveau
Affiliation as printed
Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Internal Medicine, Division of Medical Oncology, GROW, Maastricht University Medical Center, 6229ER Maastricht, the Netherlands
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Affiliation as printed
Department of Oncology, Aarhus University Hospital, 8200 Aarhus, Denmark
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Affiliation as printed
Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
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Affiliation as printed
Department of Neurosurgery, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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Affiliation as printed
Department of Neurology, Catharina Hospital, 5623EJ Eindhoven, the Netherlands
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Elisabeth-TweeSteden Ziekenhuis
Affiliation as printed
Department of Pathology, Elisabeth-TweeSteden Hospital, 5042AD Tilburg, the Netherlands
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Affiliation as printed
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, B15 2SY Birmingham, UK
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Affiliation as printed
Systems Immunity Research Institute, Medical School, Cardiff University, CF14 4XN Cardiff, UK
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European Organisation for Research and Treatment of Cancer
Affiliation as printed
EORTC Headquarters, 1200 Brussels, Belgium
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European Organisation for Research and Treatment of Cancer
Affiliation as printed
EORTC Headquarters, 1200 Brussels, Belgium
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Affiliation as printed
Université de Liège, Department of Human Genetics, 4000 Liège, Belgium
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Affiliation as printed
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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University of Liège · University Medical Center Utrecht
Affiliation as printed
Department of Neurosurgery, UMC Utrecht, 3584CX Utrecht, the Netherlands; Université de Liège, Department of Human Genetics, 4000 Liège, Belgium
Department of Neurosurgery, UMC Utrecht, 3584CX Utrecht, the Netherlands
Université de Liège, Department of Human Genetics, 4000 Liège, Belgium
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Pim J. French corresponding
Affiliation as printed
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands. Electronic address: p.french@erasmusmc.nl
Department of Neurology, Erasmus Medical Center, 3015GD Rotterdam, the Netherlands
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