title: Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma.
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.affiliation: NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bougnaud
authors.affiliation: NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Anna
authors.initials: A
authors.lastname: Golebiewska
authors.affiliation: NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Oudin
authors.affiliation: NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Olivier
authors.initials: O
authors.lastname: Keunen
authors.affiliation: Edinger-Institute (Neurological Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Edinger-Institute (Neurological Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Mäder
authors.affiliation: NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Francisco
authors.initials: F
authors.lastname: Azuaje
authors.affiliation: NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Fritah
authors.affiliation: NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stieber
authors.affiliation: Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Tony
authors.initials: T
authors.lastname: Kaoma
authors.affiliation: Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vallar
authors.affiliation: Core Facility Flow Cytometry, Department of Immunology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Nicolaas H C
authors.initials: NH
authors.lastname: Brons
authors.affiliation: U1029 INSERM, Angiogenesis and Cancer Microenvironment Laboratory, University of Bordeaux, Talence, France.|NORLUX Neuro-Oncology, Department of Biomedicine, University of Bergen, Norway.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daubon
authors.affiliation: 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.
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.affiliation: 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.
authors.forename: Terje
authors.initials: T
authors.lastname: Sundstrøm
authors.affiliation: Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Core Facility Flow Cytometry, Department of Immunology, Luxembourg Institute of Health (L.I.H.) Luxembourg, Luxembourg.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: 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.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.affiliation: 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.
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D001808:Blood Vessels / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D000072356:Parenchymal Tissue / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D059467:Transcriptome; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D042501:Angiogenic Proteins; D016326:Extracellular Matrix Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
keywords: angiogenesis; endothelial cells; glioblastoma; patient-derived xenograft; tumour microenvironment