title: Tenascin-C Orchestrates Glioblastoma Angiogenesis by Modulation of Pro- and Anti-angiogenic Signaling.
abstract: High expression of the extracellular matrix component tenascin-C in the tumor microenvironment correlates with decreased patient survival. Tenascin-C promotes cancer progression and a disrupted tumor vasculature through an unclear mechanism. Here, we examine the angiomodulatory role of tenascin-C. We find that direct contact of endothelial cells with tenascin-C disrupts actin polymerization, resulting in cytoplasmic retention of the transcriptional coactivator YAP. Tenascin-C also downregulates YAP pro-angiogenic target genes, thus reducing endothelial cell survival, proliferation, and tubulogenesis. Glioblastoma cells exposed to tenascin-C secrete pro-angiogenic factors that promote endothelial cell survival and tubulogenesis. Proteomic analysis of their secretome reveals a signature, including ephrin-B2, that predicts decreased survival of glioma patients. We find that ephrin-B2 is an important pro-angiogenic tenascin-C effector. Thus, we demonstrate dual activities for tenascin-C in glioblastoma angiogenesis and uncover potential targeting and prediction opportunities.
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Tristan
authors.initials: T
authors.lastname: Rupp
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; Institute of Molecular Medicine and Cell Research, University of Freiburg, 79104 Freiburg, Germany; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Langlois
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Koczorowska
authors.affiliation: iBV, INSERM, CNRS, Université Côte d'Azur, 06108 Nice, France.
authors.forename: Agata
authors.initials: A
authors.lastname: Radwanska
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Sun
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hussenet
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lefebvre
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Devadarssen
authors.initials: D
authors.lastname: Murdamoothoo
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Arnold
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Klein
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Biniossek
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hyenne
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Naudin
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Ines
authors.initials: I
authors.lastname: Velazquez-Quesada
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schilling
authors.affiliation: iBV, INSERM, CNRS, Université Côte d'Azur, 06108 Nice, France.
authors.forename: Ellen
authors.initials: E
authors.lastname: Van Obberghen-Schilling
authors.affiliation: The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, INSERM U1109 - MN3T, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France. Electronic address: gertraud.orend@inserm.fr.
authors.forename: Gertraud
authors.initials: G
authors.lastname: Orend
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D036388:Ephrin-B2 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D040901:Proteomics; D015398:Signal Transduction; D019063:Tenascin / Q000008:administration & dosage*; D014157:Transcription Factors / Q000235:genetics*; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D036388:Ephrin-B2; D009687:Nuclear Proteins; D019063:Tenascin; D014157:Transcription Factors; C456659:YY1AP1 protein, human
keywords: angio-modulatory secretome; angiogenesis; cancer; extracellular matrix; glioblastoma; proteomics; tenascin-C; tumor microenvironment