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Medulloblastoma: experimental models and reality

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Abstract

Medulloblastoma is the most frequent malignant brain tumor in childhood, but it may also affect infants, adolescents, and young adults. Recent advances in the understanding of the disease have shed light on molecular and clinical heterogeneity, which is now reflected in the updated WHO classification of brain tumors. At the same time, it is well accepted that preclinical research and clinical trials have to be subgroup-specific. Hence, valid models have to be generated specifically for every medulloblastoma subgroup to properly mimic molecular fingerprints, clinical features, and responsiveness to targeted therapies. This review summarizes the availability of experimental medulloblastoma models with a particular focus on how well these models reflect the actual disease subgroup. We further describe technical advantages and disadvantages of the models and finally point out how some models have successfully been used to introduce new drugs and why some medulloblastoma subgroups are extraordinary difficult to model.

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References

  1. Adamson DC, Shi Q, Wortham M, Northcott PA, Di C, Duncan CG, Li J, McLendon RE, Bigner DD, Taylor MD et al (2010) OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas. Cancer Res 70:181–191. doi:10.1158/0008-5472

    Article  CAS  PubMed  Google Scholar 

  2. Aldosari N, Bigner SH, Burger PC, Becker L, Kepner JL, Friedman HS, McLendon RE (2002) MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children’s Oncology Group. Arch Pathol Lab Med 126:540–544. doi:10.1043/0003-9985(2002)126

    PubMed  Google Scholar 

  3. Ayrault O, Zhao H, Zindy F, Qu C, Sherr CJ, Roussel MF (2010) Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells. Cancer Res 70:5618–5627. doi:10.1158/0008-5472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ben Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordadze PR, Guo Q, Matzuk MM, Zoghbi HY (1997) Math1 is essential for genesis of cerebellar granule neurons. Nature 390:169–172

    Article  CAS  PubMed  Google Scholar 

  5. Binning MJ, Niazi T, Pedone CA, Lal B, Eberhart CG, Kim KJ, Laterra J, Fults DW (2008) Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth. Cancer Res 68:7838–7845. doi:10.1158/0008-5472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Browd SR, Kenney AM, Gottfried ON, Yoon JW, Walterhouse D, Pedone CA, Fults DW (2006) N-myc can substitute for insulin-like growth factor signaling in a mouse model of sonic hedgehog-induced medulloblastoma. Cancer Res 66:2666–2672. doi:10.1158/0008-5472

    Article  CAS  PubMed  Google Scholar 

  7. Brown HG, Kepner JL, Perlman EJ, Friedman HS, Strother DR, Duffner PK, Kun LE, Goldthwaite PT, Burger PC (2000) “Large cell/anaplastic” medulloblastomas: a Pediatric Oncology Group Study. J Neuropathol Exp Neurol 59:857–865

    Article  CAS  PubMed  Google Scholar 

  8. Bunt J, Hasselt NE, Zwijnenburg DA, Koster J, Versteeg R, Kool M (2011) Joint binding of OTX2 and MYC in promotor regions is associated with high gene expression in medulloblastoma. PLoS One 6:e26058. doi:10.1371/journal.pone.0026058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS et al (2017) Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 31(737–754):e736. doi:10.1016/j.ccell.2017.05.005

    Google Scholar 

  10. Chlapek P, Zitterbart K, Kren L, Filipova L, Sterba J, Veselska R (2017) Uniformity under in vitro conditions: changes in the phenotype of cancer cell lines derived from different medulloblastoma subgroups. PLoS One 12:e0172552. doi:10.1371/journal.pone.0172552

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cho Y-J, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V, Goumnerova L, Eberhart CG et al (2011) Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29:1424–1430

    Article  PubMed  Google Scholar 

  12. Collier LS, Largaespada DA (2005) Hopping around the tumor genome: transposons for cancer gene discovery. Cancer Res 65:9607–9610. doi:10.1158/0008-5472

    Article  CAS  PubMed  Google Scholar 

  13. Dey J, Ditzler S, Knoblaugh SE, Hatton BA, Schelter JM, Cleary MA, Mecham B, Rorke-Adams LB, Olson JM (2012) A distinct Smoothened mutation causes severe cerebellar developmental defects and medulloblastoma in a novel transgenic mouse model. Mol Cell Biol 32:4104–4115. doi:10.1128/MCB.00862-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fiaschetti G, Castelletti D, Zoller S, Schramm A, Schroeder C, Nagaishi M, Stearns D, Mittelbronn M, Eggert A, Westermann F et al (2011) Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma. Oncogene 30:2823–2835. doi:10.1038/onc.2011.10

    Article  CAS  PubMed  Google Scholar 

  15. Frappart PO, Lee Y, Lamont J, McKinnon PJ (2007) BRCA2 is required for neurogenesis and suppression of medulloblastoma. EMBO J 26:2732–2742. doi:10.1038/sj.emboj.7601703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Friedman HS, Burger PC, Bigner SH, Trojanowski JQ, Brodeur GM, He XM, Wikstrand CJ, Kurtzberg J, Berens ME, Halperin EC (1988) Phenotypic and genotypic analysis of a human medulloblastoma cell line and transplantable xenograft (D341 Med) demonstrating amplification of c-myc. Am J Pathol 130:472–484

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Friedman HS, Burger PC, Bigner SH, Trojanowski JQ, Wikstrand CJ, Halperin EC, Bigner DD (1985) Establishment and characterization of the human medulloblastoma cell line and transplantable xenograft D283 Med. J Neuropathol Exp Neurol 44:592–605

    Article  CAS  PubMed  Google Scholar 

  18. Fults D, Pedone C, Dai C, Holland EC (2002) MYC expression promotes the proliferation of neural progenitor cells in culture and in vivo. Neoplasia 4:32–39. doi:10.1038/sj/neo/7900200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fults DW (2005) Modeling medulloblastoma with genetically engineered mice. Neurosurg Focus 19:E7

    Article  PubMed  Google Scholar 

  20. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, Kranenburg TA, Hogg T, Poppleton H, Martin J et al (2010) Subtypes of medulloblastoma have distinct developmental origins. Nature 468:1095–1099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–1113

    Article  CAS  PubMed  Google Scholar 

  22. Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Grammel D, Warmuth-Metz M, von Bueren AO, Kool M, Pietsch T, Kretzschmar HA, Rowitch DH, Rutkowski S, Pfister SM, Schüller U (2012) Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathol 123:601–614. doi:10.1007/s00401-012-0961-0

    Article  CAS  PubMed  Google Scholar 

  24. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S et al (1996) Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85:841–851

    Article  CAS  PubMed  Google Scholar 

  25. Hahn H, Wojnowski L, Specht K, Kappler R, Calzada-Wack J, Potter D, Zimmer A, Muller U, Samson E, Quintanilla-Martinez L et al (2000) Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J Biol Chem 275:28341–28344. doi:10.1074/jbc.C000352200

    Article  CAS  PubMed  Google Scholar 

  26. Hallahan AR, Pritchard JI, Hansen S, Benson M, Stoeck J, Hatton BA, Russell TL, Ellenbogen RG, Bernstein ID, Beachy PA et al (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64:7794–7800

    Article  CAS  PubMed  Google Scholar 

  27. He XM, Wikstrand CJ, Friedman HS, Bigner SH, Pleasure S, Trojanowski JQ, Bigner DD (1991) Differentiation characteristics of newly established medulloblastoma cell lines (D384 Med, D425 Med, and D458 Med) and their transplantable xenografts. Lab Invest 64:833–843

    CAS  PubMed  Google Scholar 

  28. Helms AW, Abney AL, Ben-Arie N, Zoghbi HY, Johnson JE (2000) Autoregulation and multiple enhancers control Math1 expression in the developing nervous system. Development 127:1185–1196

    CAS  PubMed  Google Scholar 

  29. Hill RM, Kuijper S, Lindsey JC, Petrie K, Schwalbe EC, Barker K, Boult JK, Williamson D, Ahmad Z, Hallsworth A et al (2015) Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. Cancer Cell 27:72–84. doi:10.1016/j.ccell.2014.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Holcomb VB, Vogel H, Marple T, Kornegay RW, Hasty P (2006) Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs. Oncogene 25:7159–7165. doi:10.1038/sj.onc.1209704

    Article  CAS  PubMed  Google Scholar 

  31. Hovestadt V, Jones DT, Picelli S, Wang W, Kool M, Northcott PA, Sultan M, Stachurski K, Ryzhova M, Warnatz HJ et al (2014) Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510:537–541. doi:10.1038/nature13268

    Article  CAS  PubMed  Google Scholar 

  32. Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, Cavalli FM, Ramaswamy V, Zapatka M, Reifenberger G et al (2013) Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol 125:913–916. doi:10.1007/s00401-013-1126-5

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ivanov DP, Coyle B, Walker DA, Grabowska AM (2016) In vitro models of medulloblastoma: choosing the right tool for the job. J Biotechnol 236:10–25. doi:10.1016/j.jbiotec.2016.07.028

    Article  CAS  PubMed  Google Scholar 

  34. Jacobsen PF, Jenkyn DJ, Papadimitriou JM (1985) Establishment of a human medulloblastoma cell line and its heterotransplantation into nude mice. J Neuropathol Exp Neurol 44:472–485

    Article  CAS  PubMed  Google Scholar 

  35. Jenkins NC, Rao G, Eberhart CG, Pedone CA, Dubuc AM, Fults DW (2016) Somatic cell transfer of c-Myc and Bcl-2 induces large-cell anaplastic medulloblastomas in mice. J Neurooncol 126:415–424. doi:10.1007/s11060-015-1985-9

    Article  CAS  PubMed  Google Scholar 

  36. Kawauchi D, Robinson G, Uziel T, Gibson P, Rehg J, Gao C, Finkelstein D, Qu C, Pounds S, Ellison DW et al (2012) A mouse model of the most aggressive subgroup of human medulloblastoma. Cancer Cell 21:168–180. doi:10.1016/j.ccr.2011.12.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Koch A, Waha A, Tonn JC, Sörensen N, Berthold F, Wolter M, Reifenberger J, Hartmann W, Friedl W, Reifenberger G et al (2001) Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 93:445–449

    Article  CAS  PubMed  Google Scholar 

  38. Kool M, Jones DT, Jäger N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M et al (2014) Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25:393–405. doi:10.1016/j.ccr.2014.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, Troost D, Meeteren NS, Caron HN, Cloos J et al (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3:e3088

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lee Y, Kawagoe R, Sasai K, Li Y, Russell HR, Curran T, McKinnon PJ (2007) Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26:6442–6447 (pii:1210467)

    Article  CAS  PubMed  Google Scholar 

  41. Lee Y, McKinnon PJ (2002) DNA ligase IV suppresses medulloblastoma formation. Cancer Res 62:6395–6399

    CAS  PubMed  Google Scholar 

  42. Lin CY, Erkek S, Tong Y, Yin L, Federation AJ, Zapatka M, Haldipur P, Kawauchi D, Risch T, Warnatz HJ et al (2016) Active medulloblastoma enhancers reveal subgroup-specific cellular origins. Nature 530:57–62. doi:10.1038/nature16546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lin W, Kemper A, McCarthy KD, Pytel P, Wang JP, Campbell IL, Utset MF, Popko B (2004) Interferon-gamma induced medulloblastoma in the developing cerebellum. J Neurosci 24:10074–10083. doi:10.1523/JNEUROSCI.2604-04.2004

    Article  CAS  PubMed  Google Scholar 

  44. Morrissy AS, Cavalli FMG, Remke M, Ramaswamy V, Shih DJH, Holgado BL, Farooq H, Donovan LK, Garzia L, Agnihotri S et al (2017) Spatial heterogeneity in medulloblastoma. Nat Genet. doi:10.1038/ng.3838

    PubMed  PubMed Central  Google Scholar 

  45. Morrissy AS, Garzia L, Shih DJ, Zuyderduyn S, Huang X, Skowron P, Remke M, Cavalli FM, Ramaswamy V, Lindsay PE et al (2016) Divergent clonal selection dominates medulloblastoma at recurrence. Nature 529:351–357. doi:10.1038/nature16478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Northcott PA, Hielscher T, Dubuc A, Mack S, Shih D, Remke M, Al-Halabi H, Albrecht S, Jabado N, Eberhart CG et al (2011) Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol 122:231–240. doi:10.1007/s00401-011-0846-7

    Article  PubMed  PubMed Central  Google Scholar 

  47. Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P et al (2011) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29:1408–1414. doi:10.1200/JCO.2009.27.4324

    Article  PubMed  Google Scholar 

  48. Northcott PA, Lee C, Zichner T, Stutz AM, Erkek S, Kawauchi D, Shih DJ, Hovestadt V, Zapatka M, Sturm D et al (2014) Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511:428–434. doi:10.1038/nature13379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T et al (2003) Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst 95:1548–1551

    Article  CAS  PubMed  Google Scholar 

  50. Othman RT, Kimishi I, Bradshaw TD, Storer LC, Korshunov A, Pfister SM, Grundy RG, Kerr ID, Coyle B (2014) Overcoming multiple drug resistance mechanisms in medulloblastoma. Acta Neuropathol Commun 2:57. doi:10.1186/2051-5960-2-57

    Article  PubMed  PubMed Central  Google Scholar 

  51. Pastorino L, Ghiorzo P, Nasti S, Battistuzzi L, Cusano R, Marzocchi C, Garre ML, Clementi M, Scarra GB (2009) Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am J Med Genet A 149A:1539–1543. doi:10.1002/ajmg.a.32944

    Article  CAS  PubMed  Google Scholar 

  52. Pei Y, Moore CE, Wang J, Tewari AK, Eroshkin A, Cho YJ, Witt H, Korshunov A, Read TA, Sun JL et al (2012) An animal model of MYC-driven medulloblastoma. Cancer Cell 21:155–167. doi:10.1016/j.ccr.2011.12.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Phoenix TN, Patmore DM, Boop S, Boulos N, Jacus MO, Patel YT, Roussel MF, Finkelstein D, Goumnerova L, Perreault S et al (2016) Medulloblastoma genotype dictates blood brain barrier phenotype. Cancer Cell 29:508–522. doi:10.1016/j.ccell.2016.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pietsch T, Scharmann T, Fonatsch C, Schmidt D, Ockler R, Freihoff D, Albrecht S, Wiestler OD, Zeltzer P, Riehm H (1994) Characterization of five new cell lines derived from human primitive neuroectodermal tumors of the central nervous system. Cancer Res 54:3278–3287

    CAS  PubMed  Google Scholar 

  55. Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, Sörensen N, Berthold F, Henk B, Schmandt N et al (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57:2085–2088

    CAS  PubMed  Google Scholar 

  56. Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C et al (2002) Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415:436–442

    Article  CAS  PubMed  Google Scholar 

  57. Pöschl J, Koch A, Schüller U (2015) Histological subtype of medulloblastoma frequently changes upon recurrence. Acta Neuropathol 129:459–461. doi:10.1007/s00401-015-1397-0

    Article  PubMed  Google Scholar 

  58. Pöschl J, Stark S, Neumann P, Grobner S, Kawauchi D, Jones DT, Northcott PA, Lichter P, Pfister SM, Kool M et al (2014) Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts. Acta Neuropathol 128:123–136. doi:10.1007/s00401-014-1297-8

    Article  PubMed  Google Scholar 

  59. Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57:842–845

    CAS  PubMed  Google Scholar 

  60. Ramaswamy V, Remke M, Bouffet E, Faria CC, Perreault S, Cho YJ, Shih DJ, Luu B, Dubuc AM, Northcott PA et al (2013) Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol 14:1200–1207. doi:10.1016/S1470-2045(13)70449-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rao G, Pedone CA, Coffin CM, Holland EC, Fults DW (2003) c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice. Neoplasia 5:198–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rao G, Pedone CA, Valle LD, Reiss K, Holland EC, Fults DW (2004) Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 23(36):6156–6162

    Article  CAS  PubMed  Google Scholar 

  63. Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, Packer RJ, Goldman S, Prados MD, Desjardins A et al (2015) Vismodegib exerts targeted efficacy against recurrent sonic hedgehog-subgroup medulloblastoma: results from Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J Clin Oncol 33:2646–2654. doi:10.1200/JCO.2014.60.1591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B et al (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 361:1173–1178 (pii:NEJMoa0902903)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Sörensen N, Graf N, Emser A, Pietsch T, Wolff JE et al (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986

    Article  CAS  PubMed  Google Scholar 

  66. Sanden E, Dyberg C, Krona C, Gallo-Oller G, Olsen TK, Enriquez Perez J, Wickstrom M, Estekizadeh A, Kool M, Visse E et al (2017) Establishment and characterization of an orthotopic patient-derived Group 3 medulloblastoma model for preclinical drug evaluation. Sci Rep 7:46366. doi:10.1038/srep46366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sasai K, Romer JT, Lee Y, Finkelstein D, Fuller C, McKinnon PJ, Curran T (2006) Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies. Cancer Res 66:4215–4222. doi:10.1158/0008-5472

    Article  CAS  PubMed  Google Scholar 

  68. Schüller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG, Huillard E, Sun T, Ligon AH, Qian Y et al (2008) Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14:123–134

    Article  PubMed  PubMed Central  Google Scholar 

  69. Schwalbe EC, Lindsey JC, Nakjang S, Crosier S, Smith AJ, Hicks D, Rafiee G, Hill RM, Iliasova A, Stone T et al (2017) Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol. doi:10.1016/S1470-2045(17)30243-7

    PubMed  PubMed Central  Google Scholar 

  70. Sengupta S, Weeraratne SD, Sun H, Phallen J, Rallapalli SK, Teider N, Kosaras B, Amani V, Pierre-Francois J, Tang Y et al (2014) alpha5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. Acta Neuropathol 127:593–603. doi:10.1007/s00401-013-1205-7

    Article  CAS  PubMed  Google Scholar 

  71. Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W et al (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065–1076. doi:10.1016/j.cell.2013.01.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sutter R, Shakhova O, Bhagat H, Behesti H, Sutter C, Penkar S, Santuccione A, Bernays R, Heppner FL, Schüller U et al (2010) Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas. Oncogene 29:1845–1856 (pii:onc2009472)

    Article  CAS  PubMed  Google Scholar 

  73. Swartling FJ, Savov V, Persson AI, Chen J, Hackett CS, Northcott PA, Grimmer MR, Lau J, Chesler L, Perry A et al (2012) Distinct neural stem cell populations give rise to disparate brain tumors in response to N-MYC. Cancer Cell 21:601–613. doi:10.1016/j.ccr.2012.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Swartling FJ, Grimmer MR, Hackett CS, Northcott PA, Fan QW, Goldenberg DD, Lau J, Masic S, Nguyen K, Yakovenko S et al (2010) Pleiotropic role for MYCN in medulloblastoma. Genes Dev 24:1059–1072. doi:10.1101/gad.1907510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A et al (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472. doi:10.1007/s00401-011-0922-z

    Article  CAS  PubMed  Google Scholar 

  76. Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ et al (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931

    Article  CAS  PubMed  Google Scholar 

  77. Triscott J, Lee C, Foster C, Manoranjan B, Pambid MR, Berns R, Fotovati A, Venugopal C, O’Halloran K, Narendran A et al (2013) Personalizing the treatment of pediatric medulloblastoma: polo-like kinase 1 as a molecular target in high-risk children. Cancer Res 73:6734–6744. doi:10.1158/0008-5472.CAN-12-4331

    Article  CAS  PubMed  Google Scholar 

  78. Uziel T, Zindy F, Xie S, Lee Y, Forget A, Magdaleno S, Rehg JE, Calabrese C, Solecki D, Eberhart CG et al (2005) The tumor suppressors Ink4c and p53 collaborate independently with patched to suppress medulloblastoma formation. Genes Dev 19:2656–2667 (pii:gad.1368605)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang J, Pham-Mitchell N, Schindler C, Campbell IL (2003) Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-alpha-stimulated STAT2-independent production of IFN-gamma in the brain. J Clin Invest 112:535–543. doi:10.1172/JCI18637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang X, Dubuc AM, Ramaswamy V, Mack S, Gendoo DM, Remke M, Wu X, Garzia L, Luu B, Cavalli F et al (2015) Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta Neuropathol 129:449–457. doi:10.1007/s00401-015-1389-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wefers AK, Warmuth-Metz M, Poschl J, von Bueren AO, Monoranu CM, Seelos K, Peraud A, Tonn JC, Koch A, Pietsch T et al (2014) Subgroup-specific localization of human medulloblastoma based on pre-operative MRI. Acta Neuropathol 127:931–933. doi:10.1007/s00401-014-1271-5

    Article  PubMed  Google Scholar 

  82. Wetmore C, Eberhart DE, Curran T (2001) Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61:513–516

    CAS  PubMed  Google Scholar 

  83. Wu X, Northcott PA, Dubuc A, Dupuy AJ, Shih DJ, Witt H, Croul S, Bouffet E, Fults DW, Eberhart CG et al (2012) Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482:529–533. doi:10.1038/nature10825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, Schüller U, Machold R, Fishell G, Rowitch DH et al (2008) Medulloblastoma can be initiated by deletion of patched in lineage-restricted progenitors or stem cells. Cancer Cell 14:135–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zurawel RH, Chiappa SA, Allen C, Raffel C (1998) Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res 58:896–899

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Dr. R. Gilbertson for providing images on murine WNT medulloblastoma. U.S. is supported by the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg.

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Authors and Affiliations

  1. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Julia E. Neumann & Ulrich Schüller

  2. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    Fredrik J. Swartling

  3. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Ulrich Schüller

  4. Research Institute Children’s Cancer Center, Martinistrasse 52, 20251, Hamburg, Germany

    Ulrich Schüller

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  1. Julia E. Neumann
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  2. Fredrik J. Swartling
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  3. Ulrich Schüller
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Correspondence to Ulrich Schüller.

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Neumann, J.E., Swartling, F.J. & Schüller, U. Medulloblastoma: experimental models and reality. Acta Neuropathol 134, 679–689 (2017). https://doi.org/10.1007/s00401-017-1753-3

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  • DOI: https://doi.org/10.1007/s00401-017-1753-3

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