Tenascin-C Orchestrates Glioblastoma Angiogenesis by Modulation of Pro- and Anti-angiogenic Signaling

• Published in: Cell reports (Cambridge) 2016-12, Vol.17 (10), p.2607-2619
• Main Authors: Rupp, Tristan, Langlois, Benoit, Koczorowska, Maria M., Radwanska, Agata, Sun, Zhen, Hussenet, Thomas, Lefebvre, Olivier, Murdamoothoo, Devadarssen, Arnold, Christiane, Klein, Annick, Biniossek, Martin L., Hyenne, Vincent, Naudin, Elise, Velazquez-Quesada, Ines, Schilling, Oliver, Van Obberghen-Schilling, Ellen, Orend, Gertraud
• Format: Article
• Language: English
• Subjects: angio-modulatory secretome; angiogenesis; Animals; Biochemistry, Molecular Biology; cancer; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation - drug effects; Ephrin-B2 - genetics; extracellular matrix; Gene Expression Regulation, Neoplastic - drug effects; glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Life Sciences; Mice; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Nuclear Proteins - genetics; Proteomics; Signal Transduction; Tenascin - administration & dosage; tenascin-C; Transcription Factors - genetics; tumor microenvironment; Tumor Microenvironment - drug effects; Xenograft Model Antitumor Assays
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.11.012

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. [Display omitted] •Contact with tenascin-C blocks YAP signaling and endothelial cell behavior•Tenascin-C induces ephrin-B2 and a pro-angiogenic secretome in glioblastoma cells•Inhibiting ephrin-B2 signaling impairs tenascin-C pro-angiogenic activities•The tenascin-C secretome signature correlates with poor glioma patient prognosis Rupp et al. report a dual role for tenascin-C that results in a poorly functional glioblastoma vasculature. Tenascin-C blocks YAP pro-survival signaling in endothelial cells through direct contact. In glioblastoma cells, tenascin-C induces a pro-angiogenic secretome that correlates with poor glioma patient survival. Targeting the ephrin-B2/EPHB4 axis impairs tenascin-C pro-tumoral activities.