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Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma.
Oncotarget 2016; 7(22):31955-71O

Abstract

The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma.

Authors+Show Affiliations

NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.Edinger-Institute (Neurological Institute), Goethe University, Frankfurt am Main, Germany.Edinger-Institute (Neurological Institute), Goethe University, Frankfurt am Main, Germany.NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.Core Facility Flow Cytometry, Department of Immunology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.U1029 INSERM, Angiogenesis and Cancer Microenvironment Laboratory, University of Bordeaux, Talence, France. NORLUX Neuro-Oncology, Department of Biomedicine, University of Bergen, Norway.NORLUX Neuro-Oncology, Department of Biomedicine, University of Bergen, Norway. K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway. Department of Pathology, Haukeland University Hospital, Bergen, Norway.K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway. Department of Clinical Medicine K1, University of Bergen, Bergen, Norway. Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.Core Facility Flow Cytometry, Department of Immunology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg. NORLUX Neuro-Oncology, Department of Biomedicine, University of Bergen, Norway. K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg. K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27049916

Citation

Bougnaud, Sébastien, et al. "Molecular Crosstalk Between Tumour and Brain Parenchyma Instructs Histopathological Features in Glioblastoma." Oncotarget, vol. 7, no. 22, 2016, pp. 31955-71.
Bougnaud S, Golebiewska A, Oudin A, et al. Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. Oncotarget. 2016;7(22):31955-71.
Bougnaud, S., Golebiewska, A., Oudin, A., Keunen, O., Harter, P. N., Mäder, L., ... Niclou, S. P. (2016). Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. Oncotarget, 7(22), pp. 31955-71. doi:10.18632/oncotarget.7454.
Bougnaud S, et al. Molecular Crosstalk Between Tumour and Brain Parenchyma Instructs Histopathological Features in Glioblastoma. Oncotarget. 2016 May 31;7(22):31955-71. PubMed PMID: 27049916.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. AU - Bougnaud,Sébastien, AU - Golebiewska,Anna, AU - Oudin,Anaïs, AU - Keunen,Olivier, AU - Harter,Patrick N, AU - Mäder,Lisa, AU - Azuaje,Francisco, AU - Fritah,Sabrina, AU - Stieber,Daniel, AU - Kaoma,Tony, AU - Vallar,Laurent, AU - Brons,Nicolaas H C, AU - Daubon,Thomas, AU - Miletic,Hrvoje, AU - Sundstrøm,Terje, AU - Herold-Mende,Christel, AU - Mittelbronn,Michel, AU - Bjerkvig,Rolf, AU - Niclou,Simone P, PY - 2015/09/30/received PY - 2016/01/29/accepted PY - 2016/4/7/entrez PY - 2016/4/7/pubmed PY - 2017/12/21/medline KW - angiogenesis KW - endothelial cells KW - glioblastoma KW - patient-derived xenograft KW - tumour microenvironment SP - 31955 EP - 71 JF - Oncotarget JO - Oncotarget VL - 7 IS - 22 N2 - The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/27049916/Molecular_crosstalk_between_tumour_and_brain_parenchyma_instructs_histopathological_features_in_glioblastoma_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=7454 DB - PRIME DP - Unbound Medicine ER -