Transcriptome analysis reveals tumor microenvironment changes in glioblastoma

Y. Hoogstrate; K. Draaisma; S.A. Ghisai; L.V. Hijfte; N. Barin; I.D. Heer; W. Coppieters; T.P.P.V. Bosch; A. Bolleboom; Z.Y. Gao; A.J.P.E. Vincent; L. Karim; M. Deckers; M.J.B. Taphoorn; M. Kerkhof; A. Weyerbrock; M. Sanson; A. Hoeben; S. Lukacova; G. Lombardi; S. Leenstra; M. Hanse; R.E.M. Fleischeuer; C. Watts; N. Angelopoulos; T. Gorlia; V. Golfinopoulos; V. Bours; M.J.V. Bent; P.A. Robe; P.J. French

doi:10.1016/j.ccell.2023.02.019

Transcriptome analysis reveals tumor microenvironment changes in glioblastoma

Y. Hoogstrate^*, K. Draaisma, S.A. Ghisai, L.V. Hijfte, N. Barin, I.D. Heer, W. Coppieters, T.P.P.V. Bosch, A. Bolleboom, Z.Y. Gao, A.J.P.E. Vincent, L. Karim, M. Deckers, M.J.B. Taphoorn, M. Kerkhof, A. Weyerbrock, M. Sanson, A. Hoeben, S. Lukacova, G. LombardiS. Leenstra, M. Hanse, R.E.M. Fleischeuer, C. Watts, N. Angelopoulos, T. Gorlia, V. Golfinopoulos, V. Bours, M.J.V. Bent, P.A. Robe, P.J. French^*

^*Corresponding author for this work

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

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. Recur-rent 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 -in-creases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macro-phages. 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 recur-rence. 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
Number of pages	23
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

Keywords

TEMOZOLOMIDE
EVOLUTION
IMAGE
CELLS

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Hoogstrate, Y., Draaisma, K., Ghisai, S. A., Hijfte, L. V., Barin, N., Heer, I. D., Coppieters, W., Bosch, T. P. P. V., Bolleboom, A., Gao, Z. Y., 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{482ebe82d4d14f6ab41ec04a4a6e3f2f,

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. Recur-rent 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 -in-creases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macro-phages. 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 recur-rence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.",

keywords = "TEMOZOLOMIDE, EVOLUTION, IMAGE, CELLS",

author = "Y. Hoogstrate and K. Draaisma and S.A. Ghisai and L.V. Hijfte and N. Barin and I.D. Heer and W. Coppieters and T.P.P.V. Bosch and A. Bolleboom and Z.Y. Gao and A.J.P.E. Vincent and L. Karim and M. Deckers and M.J.B. Taphoorn and M. Kerkhof and A. Weyerbrock and M. Sanson and A. Hoeben and S. Lukacova and G. Lombardi and S. Leenstra and M. Hanse and R.E.M. Fleischeuer and C. Watts and N. Angelopoulos and T. Gorlia and V. Golfinopoulos and V. Bours and M.J.V. Bent and P.A. Robe and P.J. French",

note = "Funding Information: 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",

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Hoogstrate, Y, Draaisma, K, Ghisai, SA, Hijfte, LV, Barin, N, Heer, ID, Coppieters, W, Bosch, TPPV, Bolleboom, A, Gao, ZY, 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, Bent, MJV, 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, Y.

AU - Draaisma, K.

AU - Ghisai, S.A.

AU - Hijfte, L.V.

AU - Barin, N.

AU - Heer, I.D.

AU - Coppieters, W.

AU - Bosch, T.P.P.V.

AU - Bolleboom, A.

AU - Gao, Z.Y.

AU - Vincent, A.J.P.E.

AU - Karim, L.

AU - Deckers, M.

AU - Taphoorn, M.J.B.

AU - Kerkhof, M.

AU - Weyerbrock, A.

AU - Sanson, M.

AU - Hoeben, A.

AU - Lukacova, S.

AU - Lombardi, G.

AU - Leenstra, S.

AU - Hanse, M.

AU - Fleischeuer, R.E.M.

AU - Watts, C.

AU - Angelopoulos, N.

AU - Gorlia, T.

AU - Golfinopoulos, V.

AU - Bours, V.

AU - Bent, M.J.V.

AU - Robe, P.A.

AU - French, P.J.

N1 - Funding Information: 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. Recur-rent 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 -in-creases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macro-phages. 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 recur-rence. 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. Recur-rent 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 -in-creases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macro-phages. 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 recur-rence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.

KW - TEMOZOLOMIDE

KW - EVOLUTION

KW - IMAGE

KW - CELLS

U2 - 10.1016/j.ccell.2023.02.019

DO - 10.1016/j.ccell.2023.02.019

M3 - Article

C2 - 36898379

SN - 1535-6108

VL - 41

SP - 678-692.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -