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A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat

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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.

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Acknowledgments

The authors wish to thank the family of the patient for their strong support of this study. We thank Sandra Riedinger, Carina Konrad, Mathias Koch, Andreas Lacher, Diana Jäger, Sylvia Kaden, Tina Wiesner, and Andrea Wittmann for excellent technical assistance. T.M. is supported by a grant from the B. Braun Foundation; T.M., I.O., and S.M.P. by a grant from the Wilhelm Sander Foundation; H.E.D. and O.W. through the NGFNplus program by a grant of the Bundesministerium für Bildung und Forschung (BMBF), Germany; H.E.D. by the University of Heidelberg through both the FRONTIER and the OLYMPIA MORATA programs; O.B. by the EU (FP7-HEALTH-F5-2010-266753-SCR&Tox), BMBF grants 01GNO813 and 0315799 (BIODISC), BIO.NRW (project StemCellFactory), and the Hertie Foundation.

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Authors and Affiliations

  1. Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Till Milde, Hedwig E. Deubzer, Ina Oehme, Marco Lodrini & Olaf Witt

  2. Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany

    Till Milde, Hendrik Witt, Hedwig E. Deubzer, Marco Lodrini, Andreas E. Kulozik, Stefan M. Pfister & Olaf Witt

  3. Department of Neurobiology of Brain Tumors (G381), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Susanne Kleber & Ana Martin-Villalba

  4. Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany

    Andrey Korshunov & Andreas von Deimling

  5. Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Andrey Korshunov & Andreas von Deimling

  6. Division of Molecular Genetics (B060), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Hendrik Witt & Stefan M. Pfister

  7. Division of Biostatistics (C060), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Thomas Hielscher & Axel Benner

  8. Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn, Bonn, Germany

    Philipp Koch & Oliver Brüstle

  9. Department of Hematology/Oncology, University Hospital Tübingen, Tübingen, Germany

    Hans-Georg Kopp

  10. Project Group Small Animal Imaging, Division of Medical Physics in Radiology (E020), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Manfred Jugold

  11. Division of Cellular and Molecular Pathology (G130), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Hermann-Josef Gröne

  12. Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Richard J. Gilbertson

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  1. Till Milde
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  2. Susanne Kleber
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Correspondence to Till Milde.

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401_2011_866_MOESM1_ESM.xls

Supplemental Table 1 Characteristics of patients included in the gene expression profiling. PFS: progression-free survival; OS: overall survival. (XLS 23 kb)

Supplemental Table 2 Antibodies used in this study (XLS 23 kb)

Supplemental Table 3 Primers used in this study. F: forward primer; R: reverse primer. (XLS 24 kb)

401_2011_866_MOESM4_ESM.xls

Supplemental Table 4 Calculation of half-maximal effective concentration (EC50), published maximal peak plasma concentrations (max PPC), calculation of EC50/max PPC ratios; HDACi: histone deacetylase inhibitor; VPA: valproic acid; VCR: vincristine; CDDP: cisplatin; TMZ: temozolomide. (XLS 16 kb)

401_2011_866_MOESM5_ESM.ppt

Supplemental Fig. 1 DKFZ-EP1NS forms tumors in vivo in a niche-dependent manner. a Subcutaneously injected DKFZ-EP1NS cells form tumors with histology (right panel) reminiscent of the histology of the subcutaneous metastasis of the patient (left panel), recapitulating the tumor in a niche-dependent manner (original magnification: 100×). Of note, the subcutaneous tumors in mice display a clear cell phenotype, as did the patient’s subcutaneous metastasis. b Intraperitoneally injected DKFZ-EP1NS cells in Matrigel form tumors with compact small round cells, with no morphological correlate in the patient (original magnification: 100×) (PPT 346 kb)

401_2011_866_MOESM6_ESM.ppt

Supplemental Fig. 2 Immunohistochemical staining for epithelial membrane antigen (EMA), smooth muscle actin (SMA), and vimentin. EMA, SMA, and vimentin stain positive and xenografts stain comparably to the patient′s tumor. Black and white arrows indicate the typical granular staining pattern for EMA; insets show enlarged areas of the original image. Note the pattern for SMA, where an increase in positivity from patient′s primary tumor to second recurrence can be seen, with the staining intensity of the mouse 1° and 2° xenografts most closely resembling the second recurrence (original magnification : EMA: 400×; SMA and vimentin: 200×). rec: recurrence; 1°: mouse primary xenograft; 2°: mouse secondary xenograft; met: metastasis; s.c.: subcutaneous (PPT 3206 kb)

401_2011_866_MOESM7_ESM.ppt

Supplemental Fig. 3 Immunohistochemical staining for CD99, cytokeratin, S100, and synaptophysin. Both the patient′s tumor, recurrences, and metastasis as well as the mouse 1°, 2° orthotopic and subcutaneous xenograft stain negative for CD99, cytokeratin, S100, and synaptophysin (original magnification: 200×). All stainings were tested on positive controls. rec: recurrence; 1°: mouse primary xenograft; 2°: mouse secondary xenograft; met: metastasis; s.c.: subcutaneous (PPT 7,384 kb)

401_2011_866_MOESM8_ESM.ppt

Supplemental Fig. 4 DKFZ-EP1NS cells retain typical aberrations and belong to cytogenetic group 3 and molecular subgroup C. a Exemplary data of FISH analysis of late-passage (passage 30) DKFZ-EP1NS cells cultured in vitro. The left panel depicts changes at chromosome 1p, as shown by loss of one signal for 1p telomere (1pTEL, green) and for 1p36 (red), while retaining the normal two signals for 1q (1q25, aqua). The right panel depicts the monosomy of chromosome 9 (9p11-q11, green, one signal only) and homozygous loss of 9p21 (orange, no signal), the locus of CDKN2A. P30: passage 30. b Assessment of gene expression in DKFZ-EP1NS at different passages (P14-P23) indicative of molecular subgroup identity, as measured by quantitative real-time RT-PCR, relative to normal total brain control. Only genes from subgroup C are all consistently overexpressed, grouping DKFZ-EP1NS cells into subgroup C (PPT 162 kb)

401_2011_866_MOESM9_ESM.ppt

Supplemental Fig. 5 A high common proportion of upregulated genes reveals similarity of NSC and DKFZ-EP1NS cells. a Correspondence at the top (CAT) plots reveal a high degree of common proportion of upregulated clones in neural stem cells (NSC) and DKFZ-EP1NS (EP1NS), and to a lesser degree of downregulated genes in NSC and EP1NS. b CAT plots show a high common proportion of up- and downregulated clones in orthotopic and subcutaneous models, and lesser common proportion in xenografts and EP1NS. sc: subcutaneous; ot: orthotopic; primary: primary tumors (PPT 1,239 kb)

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Milde, T., Kleber, S., Korshunov, A. et al. A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat. Acta Neuropathol 122, 637–650 (2011). https://doi.org/10.1007/s00401-011-0866-3

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