A tumorsphere model of glioblastoma multiforme with intratumoral heterogeneity for quantitative analysis of cellular migration and drug response

Johann Mar Gudbergsson; Serhii Kostrikov; Kasper Bendix Johnsen; Frederikke Petrine Fliedner; Christian Brogger Stolberg; Nanna Humle; Anders Elias Hansen; Bjarne Winther Kristensen; Gunna Christiansen; Andreas Kjaer; Thomas Lars Andresen; Meg Duroux

doi:10.1016/j.yexcr.2019.03.031

A tumorsphere model of glioblastoma multiforme with intratumoral heterogeneity for quantitative analysis of cellular migration and drug response

Johann Mar Gudbergsson, Serhii Kostrikov, Kasper Bendix Johnsen, Frederikke Petrine Fliedner, Christian Brogger Stolberg, Nanna Humle, Anders Elias Hansen, Bjarne Winther Kristensen, Gunna Christiansen, Andreas Kjaer, Thomas Lars Andresen, Meg Duroux

Cluster for Molecular Imaging

7 Citationer (Scopus)

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor and is characterized by its sudden onset and invasive growth into the brain parenchyma. The invasive tumor cells evade conventional treatments and are thought to be responsible for the ubiquitous tumor regrowth. Understanding the behavior of these invasive tumor cells and their response to therapeutic agents could help improve patient outcome. In this study, we present a GBM tumorsphere migration model with high biological complexity to study migrating GBM cells in a quantitative and qualitative manner. We demonstrated that the in vitro migration model could be used to investigate both inhibition and stimulation of cell migration with oxaliplatin and GBM-derived extracellular vesicles, respectively. The intercellular heterogeneity within the GBM tumorspheres was examined by immunofluorescent staining of nestin/vimentin and GFAP, which showed nestin and vimentin being highly expressed in the periphery of tumorspheres and GFAP mostly in cells in the tumorsphere core. We further showed that this phenotypic gradient was present in vivo after implanting dissociated GBM tumorspheres, with the cells migrating away from the tumor being nestin-positive and GFAP-negative. These results indicate that GBM tumorsphere migration models, such as the one presented here, could provide a more detailed insight into GBM cell biology and prove highly relevant as a pre-clinical platform for drug screening and assessing drug response in the treatment of GBM.

Originalsprog	Engelsk
Tidsskrift	Experimental Cell Research
Vol/bind	379
Udgave nummer	1
Sider (fra-til)	73-82
ISSN	0014-4827
DOI	https://doi.org/10.1016/j.yexcr.2019.03.031
Status	Udgivet - 1 jun. 2019

Adgang til dokumentet

10.1016/j.yexcr.2019.03.031

Citationsformater

Gudbergsson, J. M., Kostrikov, S., Johnsen, K. B., Fliedner, F. P., Stolberg, C. B., Humle, N., Hansen, A. E., Kristensen, B. W., Christiansen, G., Kjaer, A., Andresen, T. L., & Duroux, M. (2019). A tumorsphere model of glioblastoma multiforme with intratumoral heterogeneity for quantitative analysis of cellular migration and drug response. Experimental Cell Research, 379(1), 73-82. https://doi.org/10.1016/j.yexcr.2019.03.031

A tumorsphere model of glioblastoma multiforme with intratumoral heterogeneity for quantitative analysis of cellular migration and drug response. / Gudbergsson, Johann Mar; Kostrikov, Serhii; Johnsen, Kasper Bendix et al.
I: Experimental Cell Research, Bind 379, Nr. 1, 01.06.2019, s. 73-82.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Gudbergsson, JM, Kostrikov, S, Johnsen, KB, Fliedner, FP, Stolberg, CB, Humle, N, Hansen, AE, Kristensen, BW, Christiansen, G, Kjaer, A, Andresen, TL & Duroux, M 2019, 'A tumorsphere model of glioblastoma multiforme with intratumoral heterogeneity for quantitative analysis of cellular migration and drug response', Experimental Cell Research, bind 379, nr. 1, s. 73-82. https://doi.org/10.1016/j.yexcr.2019.03.031

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abstract = "Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor and is characterized by its sudden onset and invasive growth into the brain parenchyma. The invasive tumor cells evade conventional treatments and are thought to be responsible for the ubiquitous tumor regrowth. Understanding the behavior of these invasive tumor cells and their response to therapeutic agents could help improve patient outcome. In this study, we present a GBM tumorsphere migration model with high biological complexity to study migrating GBM cells in a quantitative and qualitative manner. We demonstrated that the in vitro migration model could be used to investigate both inhibition and stimulation of cell migration with oxaliplatin and GBM-derived extracellular vesicles, respectively. The intercellular heterogeneity within the GBM tumorspheres was examined by immunofluorescent staining of nestin/vimentin and GFAP, which showed nestin and vimentin being highly expressed in the periphery of tumorspheres and GFAP mostly in cells in the tumorsphere core. We further showed that this phenotypic gradient was present in vivo after implanting dissociated GBM tumorspheres, with the cells migrating away from the tumor being nestin-positive and GFAP-negative. These results indicate that GBM tumorsphere migration models, such as the one presented here, could provide a more detailed insight into GBM cell biology and prove highly relevant as a pre-clinical platform for drug screening and assessing drug response in the treatment of GBM.",

keywords = "Glioblastoma, GBM, Migration, Invasion, Nestin, GFAP, Tumorsphere, Extracellular vesicles, Oxaliplatin",

author = "Gudbergsson, {Johann Mar} and Serhii Kostrikov and Johnsen, {Kasper Bendix} and Fliedner, {Frederikke Petrine} and Stolberg, {Christian Brogger} and Nanna Humle and Hansen, {Anders Elias} and Kristensen, {Bjarne Winther} and Gunna Christiansen and Andreas Kjaer and Andresen, {Thomas Lars} and Meg Duroux",

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T1 - A tumorsphere model of glioblastoma multiforme with intratumoral heterogeneity for quantitative analysis of cellular migration and drug response

AU - Gudbergsson, Johann Mar

AU - Kostrikov, Serhii

AU - Johnsen, Kasper Bendix

AU - Fliedner, Frederikke Petrine

AU - Stolberg, Christian Brogger

AU - Humle, Nanna

AU - Hansen, Anders Elias

AU - Kristensen, Bjarne Winther

AU - Christiansen, Gunna

AU - Kjaer, Andreas

AU - Andresen, Thomas Lars

AU - Duroux, Meg

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor and is characterized by its sudden onset and invasive growth into the brain parenchyma. The invasive tumor cells evade conventional treatments and are thought to be responsible for the ubiquitous tumor regrowth. Understanding the behavior of these invasive tumor cells and their response to therapeutic agents could help improve patient outcome. In this study, we present a GBM tumorsphere migration model with high biological complexity to study migrating GBM cells in a quantitative and qualitative manner. We demonstrated that the in vitro migration model could be used to investigate both inhibition and stimulation of cell migration with oxaliplatin and GBM-derived extracellular vesicles, respectively. The intercellular heterogeneity within the GBM tumorspheres was examined by immunofluorescent staining of nestin/vimentin and GFAP, which showed nestin and vimentin being highly expressed in the periphery of tumorspheres and GFAP mostly in cells in the tumorsphere core. We further showed that this phenotypic gradient was present in vivo after implanting dissociated GBM tumorspheres, with the cells migrating away from the tumor being nestin-positive and GFAP-negative. These results indicate that GBM tumorsphere migration models, such as the one presented here, could provide a more detailed insight into GBM cell biology and prove highly relevant as a pre-clinical platform for drug screening and assessing drug response in the treatment of GBM.

AB - Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor and is characterized by its sudden onset and invasive growth into the brain parenchyma. The invasive tumor cells evade conventional treatments and are thought to be responsible for the ubiquitous tumor regrowth. Understanding the behavior of these invasive tumor cells and their response to therapeutic agents could help improve patient outcome. In this study, we present a GBM tumorsphere migration model with high biological complexity to study migrating GBM cells in a quantitative and qualitative manner. We demonstrated that the in vitro migration model could be used to investigate both inhibition and stimulation of cell migration with oxaliplatin and GBM-derived extracellular vesicles, respectively. The intercellular heterogeneity within the GBM tumorspheres was examined by immunofluorescent staining of nestin/vimentin and GFAP, which showed nestin and vimentin being highly expressed in the periphery of tumorspheres and GFAP mostly in cells in the tumorsphere core. We further showed that this phenotypic gradient was present in vivo after implanting dissociated GBM tumorspheres, with the cells migrating away from the tumor being nestin-positive and GFAP-negative. These results indicate that GBM tumorsphere migration models, such as the one presented here, could provide a more detailed insight into GBM cell biology and prove highly relevant as a pre-clinical platform for drug screening and assessing drug response in the treatment of GBM.

KW - Glioblastoma

KW - GBM

KW - Migration

KW - Invasion

KW - Nestin

KW - GFAP

KW - Tumorsphere

KW - Extracellular vesicles

KW - Oxaliplatin

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DO - 10.1016/j.yexcr.2019.03.031

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