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Neuroblastoma Pathogenesis

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Neuroblastoma

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Abstract

Neuroblastoma is an embryonal neoplasm of the peripheral sympathetic nervous system and is therefore observed at various locations, occurring either in sympathetic ganglia or in adrenal medulla. These tissues are formed from trunk neural crest cells during development, suggesting that neuroblastoma is a cancer of neural crest-derived progenitor cells in the sympathetic nervous system. Neuroblastoma occurs mostly as sporadic cases, but some tumors are observed in familial or syndromic forms. Study of the tumor genetic alterations occurring in these various contexts has revealed the role of key genes in neuroblastoma pathogenesis. This chapter will particularly focus on the involvement of the PHOX2B, MYCN, ALK, TERT, ATRX, and LIN28B genes in various forms of the disease. It will also address the role of noncoding RNAs in neuroblastoma pathogenesis. Metastatic stage 4 neuroblastoma cases represent a high-risk disease and a clinical challenge; however, few insights into the pathogenesis of these specific forms and the genes involved in metastasis have been identified so far. This is due at least in part to the difficulty of developing relevant preclinical neuroblastoma models presenting with metastasis. Very recent studies in the chick and zebrafish model organisms highlighted the LMO1 and SEMA3C genes as potential important genes involved in the metastatic process. Finally, this chapter will discuss recent progress into the understanding of neuroblastoma pathogenesis linked to cell identity and plasticity features characterized through the analysis of epigenetic marks.

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References

  1. Le Douarin N. The neural crest. Cambridge: Cambridge University Press; 1982.

    Google Scholar 

  2. Bronner ME, Simões-Costa M. The neural crest migrating into the twenty-first century. Curr Top Dev Biol. 2016;116:115–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Furlan A, Dyachuk V, Kastriti ME, et al. Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla. Science. 2017;357:eaal3753. https://doi.org/10.1126/science.aal3753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Qualman SJ, Green WR, Brovall C, Leventhal BG. Neurofibromatosis and associated neuroectodermal tumors: a congenital neurocristopathy. Pediatr Pathol. 1986;5:65–78.

    Article  CAS  PubMed  Google Scholar 

  5. Roshkow JE, Haller JO, Berdon WE, Sane SM. Hirschsprung’s disease, Ondine’s curse, and neuroblastoma--manifestations of neurocristopathy. Pediatr Radiol. 1988;19:45–9.

    Article  CAS  PubMed  Google Scholar 

  6. Spengler CM, Gozal D, Shea SA. Chemoreceptive mechanisms elucidated by studies of congenital central hypoventilation syndrome. Respir Physiol. 2001;129:247–55.

    Article  CAS  PubMed  Google Scholar 

  7. Schneider C, Wicht H, Enderich J, Wegner M, Rohrer H. Bone morphogenetic proteins are required in vivo for the generation of sympathetic neurons. Neuron. 1999;24:861–70.

    Article  CAS  PubMed  Google Scholar 

  8. Rohrer H. Transcriptional control of differentiation and neurogenesis in autonomic ganglia. Eur J Neurosci. 2011;34:1563–73.

    Article  PubMed  Google Scholar 

  9. Amiel J, Laudier B, Attie-Bitach T, et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003;33:459–61.

    Article  CAS  PubMed  Google Scholar 

  10. Cowling VH, Chandriani S, Whitfield ML, Cole MD. A conserved Myc protein domain, MBIV, regulates DNA binding, apoptosis, transformation, and G2 arrest. Mol Cell Biol. 2006;26:4226–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sarid J, Halazonetis TD, Murphy W, Leder P. Evolutionarily conserved regions of the human c-myc protein can be uncoupled from transforming activity. Proc Natl Acad Sci. 1987;84:170–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hallberg B, Palmer RH. The role of the ALK receptor in cancer biology. Ann Oncol. 2016;27(Suppl 3):iii4–iii15.

    Article  PubMed  Google Scholar 

  13. Balzeau J, Menezes MR, Cao S, Hagan JP. The LIN28/let-7 pathway in cancer. Front Genet. 2017;8:31. https://doi.org/10.3389/fgene.2017.00031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF. The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature. 1999;399:366–70.

    Article  CAS  PubMed  Google Scholar 

  15. McConville C, Reid S, Baskcomb L, Douglas J, Rahman N. PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations. Am J Med Genet A. 2006;140:1297–301.

    Article  PubMed  CAS  Google Scholar 

  16. Mosse YP, Laudenslager M, Khazi D, Carlisle AJ, Winter CL, Rappaport E, Maris JM. Germline PHOX2B mutation in hereditary neuroblastoma. Am J Hum Genet. 2004;75:727–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Raabe EH, Laudenslager M, Winter C, Wasserman N, Cole K, LaQuaglia M, Maris DJ, Mosse YP, Maris JM. Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. Oncogene. 2008;27:469–76.

    Article  CAS  PubMed  Google Scholar 

  18. Trochet D, Bourdeaut F, Janoueix-Lerosey I, et al. Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am J Hum Genet. 2004;74:761–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Trochet D, O’Brien LM, Gozal D, et al. PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am J Hum Genet. 2005;76:421–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Trochet D, Hong SJ, Lim JK, Brunet J-F, Munnich A, Kim K-S, Lyonnet S, Goridis C, Amiel J. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum Mol Genet. 2005;14:3697–708.

    Article  CAS  PubMed  Google Scholar 

  21. Reiff T, Tsarovina K, Majdazari A, Schmidt M, del Pino I, Rohrer H. Neuroblastoma phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons. J Neurosci. 2010;30:905–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nagashimada M, Ohta H, Li C, Nakao K, Uesaka T, Brunet J-F, Amiel J, Trochet D, Wakayama T, Enomoto H. Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression. J Clin Invest. 2012;122:3145–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 1997;16:2985–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Althoff K, Beckers A, Bell E, et al. A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies. Oncogene. 2015;34:3357–68.

    Article  CAS  PubMed  Google Scholar 

  25. Berry T, Luther W, Bhatnagar N, et al. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell. 2012;22:117–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Heukamp LC, Thor T, Schramm A, et al. Targeted expression of mutated ALK induces neuroblastoma in transgenic mice. Sci Transl Med. 2012;4:141ra91.

    Article  PubMed  CAS  Google Scholar 

  27. Cazes A, Lopez-Delisle L, Tsarovina K, et al. Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma. Oncotarget. 2014;5:2688–702.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Molenaar JJ, Domingo-Fernández R, Ebus ME, et al. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nat Genet. 2012;44:1199–206.

    Article  CAS  PubMed  Google Scholar 

  29. Teitz T, Inoue M, Valentine MB, et al. Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis. Cancer Res. 2013;73:4086–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pei D, Luther W, Wang W, Paw BH, Stewart RA, George RE. Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models. PLoS Genet. 2013;9:e1003533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van Limpt V, Schramm A, van Lakeman A, Sluis P, Chan A, van Noesel M, Baas F, Caron H, Eggert A, Versteeg R. The Phox2B homeobox gene is mutated in sporadic neuroblastomas. Oncogene. 2004;23:9280–8.

    Article  PubMed  CAS  Google Scholar 

  32. Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984;224:1121–4.

    Article  CAS  PubMed  Google Scholar 

  33. Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY, Hammond D. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985;313:1111–6.

    Article  CAS  PubMed  Google Scholar 

  34. Charron J, Malynn BA, Fisher P, Stewart V, Jeannotte L, Goff SP, Robertson EJ, Alt FW. Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene. Genes Dev. 1992;6:2248–57.

    Article  CAS  PubMed  Google Scholar 

  35. Knoepfler PS, Cheng PF, Eisenman RN. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 2002;16:2699–712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Maurer J, Fuchs S, Jäger R, Kurz B, Sommer L, Schorle H. Establishment and controlled differentiation of neural crest stem cell lines using conditional transgenesis. Differ Res Biol Divers. 2007;75:580–91.

    Article  CAS  Google Scholar 

  37. Rao MS, Anderson DJ. Immortalization and controlled in vitro differentiation of murine multipotent neural crest stem cells. J Neurobiol. 1997;32:722–46.

    Article  CAS  PubMed  Google Scholar 

  38. Schulte JH, Lindner S, Bohrer A, et al. MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells. Oncogene. 2013;32:1059–65.

    Article  CAS  PubMed  Google Scholar 

  39. Olsen RR, Otero JH, García-López J, Wallace K, Finkelstein D, Rehg JE, Yin Z, Wang Y-D, Freeman KW. MYCN induces neuroblastoma in primary neural crest cells. Oncogene. 2017;36:5075. https://doi.org/10.1038/onc.2017.128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brisse HJ, Blanc T, Schleiermacher G, et al. Radiogenomics of neuroblastomas: relationships between imaging phenotypes, tumor genomic profile and survival. PLoS One. 2017;12:e0185190.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Vo KT, Matthay KK, Neuhaus J, et al. Clinical, biologic, and prognostic differences on the basis of primary tumor site in neuroblastoma: a report from the international neuroblastoma risk group project. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32:3169–76.

    Article  Google Scholar 

  42. Casey MJ, Stewart RA. Zebrafish as a model to study neuroblastoma development. Cell Tissue Res. 2017;372:223. https://doi.org/10.1007/s00441-017-2702-0.

    Article  CAS  PubMed  Google Scholar 

  43. Zhu S, Lee JS, Guo F, et al. Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell. 2012;21:362–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Burkhart CA, Cheng AJ, Madafiglio J, Kavallaris M, Mili M, Marshall GM, Weiss WA, Khachigian LM, Norris MD, Haber M. Effects of MYCN antisense oligonucleotide administration on tumorigenesis in a murine model of neuroblastoma. J Natl Cancer Inst. 2003;95:1394–403.

    Article  PubMed  Google Scholar 

  45. Sjostrom SK, Finn G, Hahn WC, Rowitch DH, Kenney AM. The Cdk1 complex plays a prime role in regulating N-myc phosphorylation and turnover in neural precursors. Dev Cell. 2005;9:327–38.

    Article  CAS  PubMed  Google Scholar 

  46. Adhikary S, Eilers M. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol. 2005;6:635–45.

    Article  CAS  PubMed  Google Scholar 

  47. Welcker M, Orian A, Jin J, Grim JE, Grim JA, Harper JW, Eisenman RN, Clurman BE. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci U S A. 2004;101:9085–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chesler L, Schlieve C, Goldenberg DD, Kenney A, Kim G, McMillan A, Matthay KK, Rowitch D, Weiss WA. Inhibition of phosphatidylinositol 3-kinase destabilizes mycn protein and blocks malignant progression in neuroblastoma. Cancer Res. 2006;66:8139–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Giet R, Prigent C. Aurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases. J Cell Sci. 1999;112(Pt 21):3591–601.

    CAS  PubMed  Google Scholar 

  50. Otto T, Horn S, Brockmann M, et al. Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell. 2009;15:67–78.

    Article  CAS  PubMed  Google Scholar 

  51. Faisal A, Vaughan L, Bavetsias V, et al. The aurora kinase inhibitor CCT137690 downregulates MYCN and sensitizes MYCN-amplified neuroblastoma in vivo. Mol Cancer Ther. 2011;10:2115–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Maris JM, Morton CL, Gorlick R, et al. Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP). Pediatr Blood Cancer. 2010;55:26–34.

    PubMed  PubMed Central  Google Scholar 

  53. Mossé YP, Lipsitz E, Fox E, Teachey DT, Maris JM, Weigel B, Adamson PC, Ingle MA, Ahern CH, Blaney SM. Pediatric phase I trial and pharmacokinetic study of MLN8237, an investigational oral selective small-molecule inhibitor of Aurora kinase A: a Children’s Oncology Group Phase I Consortium study. Clin Cancer Res. 2012;18:6058–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Manfredi MG, Ecsedy JA, Meetze KA, et al. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci U S A. 2007;104:4106–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Brockmann M, Poon E, Berry T, et al. Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer Cell. 2013;24:75–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gustafson WC, Meyerowitz JG, Nekritz EA, et al. Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell. 2014;26:414–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Richards MW, Burgess SG, Poon E, Carstensen A, Eilers M, Chesler L, Bayliss R. Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. Proc Natl Acad Sci U S A. 2016;113:13726–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lipsitz EG, Nguyen V, Zhao H, Ecsedy J, Maris JM, Adamson PC, Mosse YP. Modeling MLN8237, an aurora kinase a inhibitor, with irinotecan (IRN) and temozolomide (TMZ) in neuroblastoma (NB). J Clin Oncol. 2010;28:10593.

    Article  Google Scholar 

  59. DuBois SG, Marachelian A, Fox E, et al. Phase I study of the aurora a kinase inhibitor alisertib in combination with irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma: a NANT (New Approaches to Neuroblastoma Therapy) trial. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34:1368–75.

    Article  CAS  Google Scholar 

  60. Puissant A, Frumm SM, Alexe G, et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013;3:308–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chen T, Dent SYR. Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat Rev Genet. 2014;15:93–106.

    Article  CAS  PubMed  Google Scholar 

  62. Kramer M, Ribeiro D, Arsenian-Henriksson M, Deller T, Rohrer H. Proliferation and survival of embryonic sympathetic neuroblasts by MYCN and activated ALK signaling. J Neurosci. 2016;36:10425–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tang Y, Gholamin S, Schubert S, et al. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 2014;20:732–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Armstrong BC, Krystal GW. Isolation and characterization of complementary DNA for N-cym, a gene encoded by the DNA strand opposite to N-myc. Cell Growth Differ. 1992;3:385–90.

    CAS  PubMed  Google Scholar 

  65. Suenaga Y, Islam SMR, Alagu J, et al. NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3β resulting in the stabilization of MYCN in human neuroblastomas. PLoS Genet. 2014;10:e1003996.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Liu PY, Atmadibrata B, Mondal S, Tee AE, Liu T. NCYM is upregulated by lncUSMycN and modulates N-Myc expression. Int J Oncol. 2016;49:2464–70.

    Article  CAS  PubMed  Google Scholar 

  67. Chen Y, Takita J, Choi YL, et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature. 2008;455:971–4.

    Article  CAS  PubMed  Google Scholar 

  68. George RE, Sanda T, Hanna M, et al. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008;455:975–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Janoueix-Lerosey I, Lequin D, Brugieres L, et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008;455:967–70.

    Article  CAS  PubMed  Google Scholar 

  70. Mosse YP, Laudenslager M, Longo L, et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008;455:930–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bellini A, Bernard V, Leroy Q, et al. Deep sequencing reveals occurrence of subclonal ALK mutations in neuroblastoma at diagnosis. Clin Cancer Res. 2015;21:4913–21.

    Article  CAS  PubMed  Google Scholar 

  72. Eleveld TF, Oldridge DA, Bernard V, et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet. 2015;47:864–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Janoueix-Lerosey I, Lopez-Delisle L, Delattre O, Rohrer H. The ALK receptor in sympathetic neuron development and neuroblastoma. Cell Tissue Res. 2018;372:325. https://doi.org/10.1007/s00441-017-2784-8.

    Article  CAS  PubMed  Google Scholar 

  74. Bilsland JG, Wheeldon A, Mead A, et al. Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications. Neuropsychopharmacology. 2008;33:685–700.

    Article  CAS  PubMed  Google Scholar 

  75. Lasek AW, Lim J, Kliethermes CL, et al. An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol. PLoS One. 2011;6:e22636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Weiss JB, Xue C, Benice T, Xue L, Morris SW, Raber J. Anaplastic lymphoma kinase and leukocyte tyrosine kinase: functions and genetic interactions in learning, memory and adult neurogenesis. Pharmacol Biochem Behav. 2012;100:566–74.

    Article  CAS  PubMed  Google Scholar 

  77. Witek B, El Wakil A, Nord C, Ahlgren U, Eriksson M, Vernersson-Lindahl E, Helland Ã…, Alexeyev OA, Hallberg B, Palmer RH. Targeted disruption of ALK reveals a potential role in hypogonadotropic hypogonadism. PLoS One. 2015;10:e0123542.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Stoica GE, Kuo A, Aigner A, et al. Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem. 2001;276:16772–9.

    Article  CAS  PubMed  Google Scholar 

  79. Stoica GE, Kuo A, Powers C, Bowden ET, Sale EB, Riegel AT, Wellstein A. Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem. 2002;277:35990–8.

    Article  CAS  PubMed  Google Scholar 

  80. Mathivet T, Mazot P, Vigny M. In contrast to agonist monoclonal antibodies, both C-terminal truncated form and full length form of Pleiotrophin failed to activate vertebrate ALK (anaplastic lymphoma kinase)? Cell Signal. 2007;19:2434–43.

    Article  CAS  PubMed  Google Scholar 

  81. Miyake I, Hakomori Y, Shinohara A, Gamou T, Saito M, Iwamatsu A, Sakai R. Activation of anaplastic lymphoma kinase is responsible for hyperphosphorylation of ShcC in neuroblastoma cell lines. Oncogene. 2002;21:5823–34.

    Article  CAS  PubMed  Google Scholar 

  82. Moog-Lutz C, Degoutin J, Gouzi JY, Frobert Y, Brunet-de Carvalho N, Bureau J, Creminon C, Vigny M. Activation and inhibition of anaplastic lymphoma kinase receptor tyrosine kinase by monoclonal antibodies and absence of agonist activity of pleiotrophin. J Biol Chem. 2005;280:26039–48.

    Article  CAS  PubMed  Google Scholar 

  83. Murray PB, Lax I, Reshetnyak A, et al. Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK. Sci Signal. 2015;8:ra6.

    Article  PubMed  CAS  Google Scholar 

  84. Guan J, Umapathy G, Yamazaki Y, et al. FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase. Elife. 2015;4:e09811.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Reshetnyak AV, Murray PB, Shi X, Mo ES, Mohanty J, Tome F, Bai H, Gunel M, Lax I, Schlessinger J. Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: hierarchy and specificity of ligand-receptor interactions. Proc Natl Acad Sci U S A. 2015;112:15862–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Reiff T, Huber L, Kramer M, Delattre O, Janoueix-Lerosey I, Rohrer H. Midkine and Alk signaling in sympathetic neuron proliferation and neuroblastoma predisposition. Development. 2011;138:4699–708.

    Article  CAS  PubMed  Google Scholar 

  87. Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, Witte DP. ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin’s lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene. 1997;14:2175–88.

    Article  CAS  PubMed  Google Scholar 

  88. Bresler SC, Weiser DA, Huwe PJ, et al. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell. 2014;26:682–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Galkin AV, Melnick JS, Kim S, et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A. 2007;104:270–5.

    Article  CAS  PubMed  Google Scholar 

  90. Zou HY, Li Q, Lee JH, et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007;67:4408–17.

    Article  CAS  PubMed  Google Scholar 

  91. Mossé YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14:472–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. de Pontual L, Kettaneh D, Gordon CT, et al. Germline gain-of-function mutations of ALK disrupt central nervous system development. Hum Mutat. 2011;32:272–6.

    Article  PubMed  Google Scholar 

  93. Zhang J, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373:2336–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Montavon G, Jauquier N, Coulon A, et al. Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells. Oncotarget. 2014;5:4452–66.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Lopez-Delisle L, Pierre-Eugène C, Louis-Brennetot C, et al. Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis. Oncogene. 2018;37:1417. https://doi.org/10.1038/s41388-017-0039-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lopez-Delisle L, Pierre-Eugène C, Bloch-Gallego E, et al. Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice. Oncotarget. 2014;5:2703–13.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Cheung N-KV, Zhang J, Lu C, et al. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA. 2012;307:1062–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Pugh TJ, Morozova O, Attiyeh EF, et al. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013;45:279–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Peifer M, Hertwig F, Roels F, et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature. 2015;526:700–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Valentijn LJ, Koster J, Zwijnenburg DA, et al. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat Genet. 2015;47:1411–4.

    Article  CAS  PubMed  Google Scholar 

  101. Dyer MA, Qadeer ZA, Valle-Garcia D, Bernstein E. ATRX and DAXX: mechanisms and mutations. Cold Spring Harb Perspect Med. 2017;7:a026567. https://doi.org/10.1101/cshperspect.a026567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Gibbons RJ, Picketts DJ, Villard L, Higgs DR. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell. 1995;80:837–45.

    Article  CAS  PubMed  Google Scholar 

  103. Bérubé NG, Mangelsdorf M, Jagla M, Vanderluit J, Garrick D, Gibbons RJ, Higgs DR, Slack RS, Picketts DJ. The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis. J Clin Invest. 2005;115:258–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Garrick D, Sharpe JA, Arkell R, Dobbie L, Smith AJH, Wood WG, Higgs DR, Gibbons RJ. Loss of Atrx affects trophoblast development and the pattern of X-inactivation in extraembryonic tissues. PLoS Genet. 2006;2:e58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Heo I, Joo C, Cho J, Ha M, Han J, Kim VN. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell. 2008;32:276–84.

    Article  CAS  PubMed  Google Scholar 

  106. Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science. 2008;320:97–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hennchen M, Stubbusch J, Abarchan-El Makhfi I, et al. Lin28B and Let-7 in the control of sympathetic neurogenesis and neuroblastoma development. J Neurosci. 2015;35:16531–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Diskin SJ, Capasso M, Schnepp RW, et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet. 2012;44:1126–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Schnepp RW, Khurana P, Attiyeh EF, et al. A LIN28B-RAN-AURKA signaling network promotes neuroblastoma tumorigenesis. Cancer Cell. 2015;28:599–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Trieselmann N, Armstrong S, Rauw J, Wilde A. Ran modulates spindle assembly by regulating a subset of TPX2 and Kid activities including Aurora A activation. J Cell Sci. 2003;116:4791–8.

    Article  CAS  PubMed  Google Scholar 

  111. Tsai M-Y, Wiese C, Cao K, Martin O, Donovan P, Ruderman J, Prigent C, Zheng Y. A Ran signalling pathway mediated by the mitotic kinase Aurora A in spindle assembly. Nat Cell Biol. 2003;5:242–8.

    Article  CAS  PubMed  Google Scholar 

  112. Schnepp RW, Diskin SJ. LIN28B: an orchestrator of oncogenic signaling in neuroblastoma. Cell Cycle. 2016;15:772–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Powers JT, Tsanov KM, Pearson DS, et al. Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma. Nature. 2016;535:246–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Chen Y, Stallings RL. Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis, differentiation, and apoptosis. Cancer Res. 2007;67:976–83.

    Article  CAS  PubMed  Google Scholar 

  115. Fontana L, Fiori ME, Albini S, et al. Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS One. 2008;3:e2236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Mestdagh P, Fredlund E, Pattyn F, et al. MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors. Oncogene. 2010;29:1394–404.

    Article  CAS  PubMed  Google Scholar 

  117. Mestdagh P, Boström A-K, Impens F, et al. The miR-17-92 microRNA cluster regulates multiple components of the TGF-β pathway in neuroblastoma. Mol Cell. 2010;40:762–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wei JS, Song YK, Durinck S, et al. The MYCN oncogene is a direct target of miR-34a. Oncogene. 2008;27:5204–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Beckers A, Van Peer G, Carter DR, et al. MYCN-targeting miRNAs are predominantly downregulated during MYCN‑driven neuroblastoma tumor formation. Oncotarget. 2015;6:5204–16.

    Article  PubMed  Google Scholar 

  120. Gibert B, Delloye-Bourgeois C, Gattolliat C-H, et al. Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma. J Natl Cancer Inst. 2014;106:dju318. https://doi.org/10.1093/jnci/dju318.

    Article  CAS  PubMed  Google Scholar 

  121. Althoff K, Lindner S, Odersky A, et al. miR-542-3p exerts tumor suppressive functions in neuroblastoma by downregulating Survivin. Int J Cancer. 2015;136:1308–20.

    Article  CAS  PubMed  Google Scholar 

  122. De Mariano M, Stigliani S, Moretti S, Parodi F, Croce M, Bernardi C, Pagano A, Tonini GP, Ferrini S, Longo L. A genome-wide microRNA profiling indicates miR-424-5p and miR-503-5p as regulators of ALK expression in neuroblastoma. Oncotarget. 2017;8:56518–32.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Pandey GK, Mitra S, Subhash S, et al. The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. Cancer Cell. 2014;26:722–37.

    Article  CAS  PubMed  Google Scholar 

  124. Maris JM, Mosse YP, Bradfield JP, et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med. 2008;358:2585–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Liu PY, Erriquez D, Marshall GM, et al. Effects of a novel long noncoding RNA, lncUSMycN, on N-Myc expression and neuroblastoma progression. J Natl Cancer Inst. 2014;106:dju113. https://doi.org/10.1093/jnci/dju113.

    Article  CAS  PubMed  Google Scholar 

  126. Daudigeos-Dubus E, LE Dret L, Rouffiac V, Bawa O, Leguerney I, Opolon P, Vassal G, Geoerger B. Establishment and characterization of new orthotopic and metastatic neuroblastoma models. In Vivo. 2014;28:425–34.

    CAS  PubMed  Google Scholar 

  127. Dickson PV, Hamner B, Ng CYC, Hall MM, Zhou J, Hargrove PW, McCarville MB, Davidoff AM. In vivo bioluminescence imaging for early detection and monitoring of disease progression in a murine model of neuroblastoma. J Pediatr Surg. 2007;42:1172–9.

    Article  PubMed  Google Scholar 

  128. Joseph J-M, Gross N, Lassau N, Rouffiac V, Opolon P, Laudani L, Auderset K, Geay J-F, Mühlethaler-Mottet A, Vassal G. In vivo echographic evidence of tumoral vascularization and microenvironment interactions in metastatic orthotopic human neuroblastoma xenografts. Int J Cancer. 2005;113:881–90.

    Article  CAS  PubMed  Google Scholar 

  129. Sartelet H, Durrieu L, Fontaine F, Nyalendo C, Haddad E. Description of a new xenograft model of metastatic neuroblastoma using NOD/SCID/Il2rg null (NSG) mice. Vivo Athens Greece. 2012;26:19–29.

    Google Scholar 

  130. Hidalgo M, Amant F, Biankin AV, et al. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 2014;4:998–1013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Stewart E, Federico SM, Chen X, et al. Orthotopic patient-derived xenografts of paediatric solid tumours. Nature. 2017;549:96–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ben-David U, Ha G, Tseng Y-Y, et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat Genet. 2017;49:1567–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wang K, Diskin SJ, Zhang H, et al. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature. 2011;469:216–20.

    Article  CAS  PubMed  Google Scholar 

  134. Oldridge DA, Wood AC, Weichert-Leahey N, et al. Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature. 2015;528:418–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhu S, Zhang X, Weichert-Leahey N, et al. LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis. Cancer Cell. 2017;32:310–323.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Delloye-Bourgeois C, Bertin L, Thoinet K, et al. Microenvironment-driven shift of cohesion/detachment balance within tumors induces a switch toward metastasis in neuroblastoma. Cancer Cell. 2017;32:427–443.e8.

    Article  CAS  PubMed  Google Scholar 

  137. Le Douarin N, Kalcheim C. The neural crest. Cambridge: Cambridge University Press; 1999.

    Book  Google Scholar 

  138. Jongbloets BC, Pasterkamp RJ. Semaphorin signalling during development. Development. 2014;141:3292–7.

    Article  CAS  PubMed  Google Scholar 

  139. Coolen MW, Stirzaker C, Song JZ, et al. Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity. Nat Cell Biol. 2010;12:235–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet. 2007;16(Spec 1):R50–9.

    Article  CAS  PubMed  Google Scholar 

  141. Bert SA, Robinson MD, Strbenac D, Statham AL, Song JZ, Hulf T, Sutherland RL, Coolen MW, Stirzaker C, Clark SJ. Regional activation of the cancer genome by long-range epigenetic remodeling. Cancer Cell. 2013;23:9–22.

    Article  CAS  PubMed  Google Scholar 

  142. Henrich K-O, Bender S, Saadati M, et al. Integrative genome-scale analysis identifies epigenetic mechanisms of transcriptional deregulation in unfavorable neuroblastomas. Cancer Res. 2016;76:5523–37.

    Article  CAS  PubMed  Google Scholar 

  143. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young RA. Super-enhancers in the control of cell identity and disease. Cell. 2013;155:934–47.

    Article  CAS  PubMed  Google Scholar 

  144. Saint-André V, Federation AJ, Lin CY, Abraham BJ, Reddy J, Lee TI, Bradner JE, Young RA. Models of human core transcriptional regulatory circuitries. Genome Res. 2016;26:385–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Boeva V, Louis-Brennetot C, Peltier A, et al. Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries. Nat Genet. 2017;49:1408–13.

    Article  CAS  PubMed  Google Scholar 

  146. van Groningen T, Koster J, Valentijn LJ, et al. Neuroblastoma is composed of two super-enhancer-associated differentiation states. Nat Genet. 2017;49:1261–6.

    Article  PubMed  CAS  Google Scholar 

  147. Ross RA, Spengler BA, Biedler JL. Coordinate morphological and biochemical interconversion of human neuroblastoma cells. J Natl Cancer Inst. 1983;71:741–7.

    CAS  PubMed  Google Scholar 

  148. Bate-Eya LT, Ebus ME, Koster J, et al. Newly-derived neuroblastoma cell lines propagated in serum-free media recapitulate the genotype and phenotype of primary neuroblastoma tumours. Eur J Cancer. 2014;50:628–37.

    Article  CAS  PubMed  Google Scholar 

  149. Schleiermacher G, Janoueix-Lerosey I, Ribeiro A, et al. Accumulation of segmental alterations determines progression in neuroblastoma. J Clin Oncol. 2010;28:3122–30.

    Article  PubMed  Google Scholar 

  150. Schleiermacher G, Javanmardi N, Bernard V, et al. Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol. 2014;32:2727–34.

    Article  CAS  PubMed  Google Scholar 

  151. Schramm A, Köster J, Assenov Y, et al. Mutational dynamics between primary and relapse neuroblastomas. Nat Genet. 2015;47:872–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

I am grateful to my colleagues Caroline Louis-Brennetot, Hermann Rohrer, and Olivier Delattre for their helpful comments on this chapter.

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Authors and Affiliations

  1. Institut Curie, SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer), Inserm U830, PSL Research University, Paris, France

    Isabelle Janoueix-Lerosey

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Correspondence to Isabelle Janoueix-Lerosey .

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  1. Department of Pediatric Surgery, Necker - Enfants Malades Hospital, Assistance Publique Hopitaux de Paris, University of Paris, Paris, France

    Sabine Sarnacki

  2. Department of Pediatric Surgery, Necker - Enfants Malades Hospital, Assistance Publique Hopitaux de Paris, University of Paris, Paris, France

    Luca Pio

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Janoueix-Lerosey, I. (2020). Neuroblastoma Pathogenesis. In: Sarnacki, S., Pio, L. (eds) Neuroblastoma. Springer, Cham. https://doi.org/10.1007/978-3-030-18396-7_3

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