TY - JOUR
T1 - Transcriptome analysis reveals tumor microenvironment changes in glioblastoma
AU - Hoogstrate, Youri
AU - Draaisma, Kaspar
AU - Barin, Nastaran
AU - Taphoorn, Martin J.B.
AU - Weyerbrock, Astrid
AU - Sanson, Marc
AU - Hoeben, Ann
AU - Lukacova, Slávka
AU - Lombardi, Giuseppe
AU - Hanse, Monique
AU - Fleischeuer, Ruth E.M.
AU - Watts, Colin
AU - Angelopoulos, Nicos
AU - Gorlia, Thierry
AU - Robe, Pierre A.
AU - French, Pim J.
PY - 2023
Y1 - 2023
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.
KW - extracellular matrix
KW - glioblastoma
KW - neurons
KW - pericytes
KW - recursive correlation
KW - RNA-seq
KW - single-nucleus RNA-seq
KW - tumor evolution
UR - http://www.scopus.com/inward/record.url?scp=85151026018&partnerID=8YFLogxK
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 -