title: The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis.
abstract: Malignant astrocytomas are highly aggressive brain tumours with poor prognosis. While a number of structural genomic changes and dysregulation of signalling pathways in gliomas have been described, the identification of biomarkers and druggable targets remains an important task for novel diagnostic and therapeutic approaches. Here, we show that the Wnt-specific secretory protein Evi (also known as GPR177/Wntless/Sprinter) is overexpressed in astrocytic gliomas. Evi/Wls is a core Wnt signalling component and a specific regulator of pan-Wnt protein secretion, affecting both canonical and non-canonical signalling. We demonstrate that its depletion in glioma and glioma-derived stem-like cells led to decreased cell proliferation and apoptosis. Furthermore, Evi/Wls silencing in glioma cells reduced cell migration and the capacity to form tumours in vivo. We further show that Evi/Wls overexpression is sufficient to promote downstream Wnt signalling. Taken together, our study identifies Evi/Wls as an essential regulator of glioma tumourigenesis, identifying a pathway-specific protein trafficking factor as an oncogene and offering novel therapeutic options to interfere with the aberrant regulation of growth factors at the site of production.
authors.affiliation: German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics and Heidelberg University, Faculty of Medicine Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany. i.augustin@dkfz.de
authors.forename: Iris
authors.initials: I
authors.lastname: Augustin
authors.forename: Violaine
authors.initials: V
authors.lastname: Goidts
authors.forename: Angelika
authors.initials: A
authors.lastname: Bongers
authors.forename: Grainne
authors.initials: G
authors.lastname: Kerr
authors.forename: Gordon
authors.initials: G
authors.lastname: Vollert
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Michael
authors.initials: M
authors.lastname: Boutros
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C549111:WLS protein, human; D051153:Wnt Proteins