[en] 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.
Disciplines :
Oncology
Author, co-author :
Bougnaud, Sébastien; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
GOLEBIEWSKA, Anna ; University of Luxembourg ; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
Oudin, Anaïs; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
Keunen, Olivier; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
Harter, Patrick N; Edinger-Institute (Neurological Institute), Goethe University, Frankfurt am Main, Germany
AZUAJE, Francisco ; University of Luxembourg ; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
FRITAH, Sabrina ; University of Luxembourg ; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
Stieber, Daniel; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
Kaoma, Tony; Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
Vallar, Laurent; Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
Brons, Nicolaas H C; Core Facility Flow Cytometry, Department of Immunology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
Daubon, Thomas; U1029 INSERM, Angiogenesis and Cancer Microenvironment Laboratory, University of Bordeaux, Talence, France ; NORLUX Neuro-Oncology, Department of Biomedicine, University of Bergen, Norway
Miletic, Hrvoje; 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
Sundstrøm, Terje; 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
Herold-Mende, Christel; Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
MITTELBRONN, Michel ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Neuropathology ; Core Facility Flow Cytometry, Department of Immunology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg
Bjerkvig, Rolf; 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
NICLOU, Simone P. ; K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
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