Oncotarget

Research Papers:

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

Sébastien Bougnaud, Anna Golebiewska, Anaïs Oudin, Olivier Keunen, Patrick N. Harter, Lisa Mäder, Francisco Azuaje, Sabrina Fritah, Daniel Stieber, Tony Kaoma, Laurent Vallar, Nicolaas H.C. Brons, Thomas Daubon, Hrvoje Miletic, Terje Sundstrøm, Christel Herold-Mende, Michel Mittelbronn, Rolf Bjerkvig and Simone P. Niclou _

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Oncotarget. 2016; 7:31955-31971. https://doi.org/10.18632/oncotarget.7454

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Abstract

Sébastien Bougnaud1, Anna Golebiewska1, Anaïs Oudin1, Olivier Keunen1, Patrick N. Harter2, Lisa Mäder2, Francisco Azuaje1, Sabrina Fritah1, Daniel Stieber1, Tony Kaoma3, Laurent Vallar3, Nicolaas H.C. Brons4, Thomas Daubon5,7, Hrvoje Miletic7,8,9, Terje Sundstrøm8,10,11, Christel Herold-Mende6, Michel Mittelbronn4, Rolf Bjerkvig1,7,8 and Simone P. Niclou1,8

1 NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg

2 Edinger-Institute (Neurological Institute), Goethe University, Frankfurt am Main, Germany

3 Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg

4 Core Facility Flow Cytometry, Department of Immunology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg

5 U1029 INSERM, Angiogenesis and Cancer Microenvironment Laboratory, University of Bordeaux, Talence, France

6 Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany

7 NORLUX Neuro-Oncology, Department of Biomedicine, University of Bergen, Norway

8 K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway

9 Department of Pathology, Haukeland University Hospital, Bergen, Norway

10 Department of Clinical Medicine K1, University of Bergen, Bergen, Norway

11 Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway

Correspondence to:

Simone P. Niclou, email:

Keywords: glioblastoma, patient-derived xenograft, tumour microenvironment, endothelial cells, angiogenesis

Received: September 30, 2015 Accepted: January 29, 2016 Published: March 25, 2016

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.


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