title: A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat.
abstract: Incompletely resectable ependymomas are associated with poor prognosis despite intensive radio- and chemotherapy. Novel treatments have been difficult to develop due to the lack of appropriate models. Here, we report on the generation of a high-risk cytogenetic group 3 and molecular group C ependymoma model (DKFZ-EP1NS) which is based on primary ependymoma cells obtained from a patient with metastatic disease. This model displays stem cell features such as self-renewal capacity, differentiation capacity, and specific marker expression. In vivo transplantation showed high tumorigenic potential of these cells, and xenografts phenotypically recapitulated the original tumor in a niche-dependent manner. DKFZ-EP1NS cells harbor transcriptome plasticity, enabling a shift from a neural stem cell-like program towards a profile of primary ependymoma tumor upon in vivo transplantation. Serial transplantation of DKFZ-EP1NS cells from orthotopic xenografts yielded secondary tumors in half the time compared with the initial transplantation. The cells were resistant to temozolomide, vincristine, and cisplatin, but responded to histone deacetylase inhibitor (HDACi) treatment at therapeutically achievable concentrations. In vitro treatment of DKFZ-EP1NS cells with the HDACi Vorinostat induced neuronal differentiation associated with loss of stem cell-specific properties. In summary, this is the first ependymoma model of a cytogenetic group 3 and molecular subgroup C ependymoma based on a human cell line with stem cell-like properties, which we used to demonstrate the differentiation-inducing therapeutic potential of HDACi.
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Heidelberg, Germany. t.milde@dkfz.de
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Susanne
authors.initials: S
authors.lastname: Kleber
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Philipp
authors.initials: P
authors.lastname: Koch
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kopp
authors.forename: Manfred
authors.initials: M
authors.lastname: Jugold
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
authors.forename: Ina
authors.initials: I
authors.lastname: Oehme
authors.forename: Marco
authors.initials: M
authors.lastname: Lodrini
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Oliver
authors.initials: O
authors.lastname: Brüstle
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Ana
authors.initials: A
authors.lastname: Martin-Villalba
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004806:Ependymoma / Q000473:pathology*; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D051379:Mice; D008954:Models, Biological; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology; D010641:Phenotype; D015173:Supratentorial Neoplasms / Q000473:pathology*; D014183:Transplantation, Heterologous; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat