Transcriptome analysis reveals tumor microenvironment changes in glioblastoma
Youri Hoogstrate (Erasmus MC)
Kaspar Draaisma ( University Medical Centre Utrecht)
Nastaran Barin (Erasmus MC, TU Delft - Mechanical Engineering)
Martin J.B. Taphoorn (Leiden University Medical Center, Haaglanden Medical Center)
Astrid Weyerbrock (University of Freiburg)
Marc Sanson (Sorbonne Université)
Ann Hoeben (Maastricht University Medical Center)
Slávka Lukacova (Århus University Hospital)
Giuseppe Lombardi (Veneto Institute of Oncology IOV-IRCCS)
Monique Hanse (Catharina Ziekenhuis)
Ruth E.M. Fleischeuer (Elisabeth-TweeSteden Hospital)
Colin Watts (University of Birmingham, College of Medical and Dental Sciences)
Nicos Angelopoulos (Cardiff University)
Thierry Gorlia (EORTC Headquarters)
Pierre A. Robe (Université de Liège, University Medical Centre Utrecht)
Pim J. French (Erasmus MC)
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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.
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