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Annual Review of Pathology: Mechanisms of Disease

Volume 16, 2021

Molecular Pathogenesis of Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with two distinct etiologies. Clonal integration of Merkel cell polyomavirus DNA into the tumor genome with persistent expression of viral T antigens causes at least 60% of all MCC. UV damage leading to highly mutated genomes causes a nonviral form of MCC. Despite these distinct etiologies, both forms of MCC are similar in presentation, prognosis, and response to therapy. At least three oncogenic transcriptional programs feature prominently in both forms of MCC driven by the virus or by mutation. Both forms of MCC have a high proliferative growth rate with increased levels of cell cycle–dependent genes due to inactivation of the tumor suppressors RB and p53, a strong MYC signature due to MYCL activation by the virus or gene amplification, and an attenuated neuroendocrine differentiation program driven by the ATOH1 transcription factor.

Keyword(s): ATOH1, INSM1, LSD1, Merkel cell polyomavirus, MYCL, neuroendocrine carcinoma
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/content/journals/10.1146/annurev-pathmechdis-012419-032817
2021-01-24
2024-04-18
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Literature Cited

  1. 1. 
    Halata Z, Grim M, Bauman KI 2003. Friedrich Sigmund Merkel and his “Merkel cell”, morphology, development, and physiology: review and new results. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 271:225–39
     [Google Scholar]
  2. 2. 
    Maricich SM, Wellnitz SA, Nelson AM, Lesniak DR, Gerling GJ et al. 2009. Merkel cells are essential for light-touch responses. Science 324:1580–82
     [Google Scholar]
  3. 3. 
    Morrison KM, Miesegaes GR, Lumpkin EA, Maricich SM 2009. Mammalian Merkel cells are descended from the epidermal lineage. Dev. Biol. 336:76–83
     [Google Scholar]
  4. 4. 
    Perdigoto CN, Bardot ES, Valdes VJ, Santoriello FJ, Ezhkova E 2014. Embryonic maturation of epidermal Merkel cells is controlled by a redundant transcription factor network. Development 141:4690–96Merkel cell development requires cooperation by the ATOH1, SOX2, and ISL1 transcription factors.
     [Google Scholar]
  5. 5. 
    Harold A, Amako Y, Hachisuka J, Bai Y, Li MY et al. 2019. Conversion of Sox2-dependent Merkel cell carcinoma to a differentiated neuron-like phenotype by T antigen inhibition. PNAS 116:20104–14Depletion of MCPyV leads to neural differentiation of MCCP cell lines.
     [Google Scholar]
  6. 6. 
    Lilo MT, Chen Y, LeBlanc RE 2018. INSM1 is more sensitive and interpretable than conventional immunohistochemical stains used to diagnose Merkel cell carcinoma. Am. J. Surg. Pathol. 42:1541–48
     [Google Scholar]
  7. 7. 
    Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C et al. 2014. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516:121–25
     [Google Scholar]
  8. 8. 
    Woo SH, Ranade S, Weyer AD, Dubin AE, Baba Y et al. 2014. Piezo2 is required for Merkel-cell mechanotransduction. Nature 509:622–26
     [Google Scholar]
  9. 9. 
    Wang L, Zhou H, Zhang M, Liu W, Deng T et al. 2019. Structure and mechanogating of the mammalian tactile channel PIEZO2. Nature 573:225–29
     [Google Scholar]
  10. 10. 
    Taberner FJ, Prato V, Schaefer I, Schrenk-Siemens K, Heppenstall PA, Lechner SG 2019. Structure-guided examination of the mechanogating mechanism of PIEZO2. PNAS 116:14260–69
     [Google Scholar]
  11. 11. 
    Logan GJ, Wright MC, Kubicki AC, Maricich SM 2018. Notch pathway signaling in the skin antagonizes Merkel cell development. Dev. Biol. 434:207–14
     [Google Scholar]
  12. 12. 
    Bardot ES, Valdes VJ, Zhang J, Perdigoto CN, Nicolis S et al. 2013. Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells. EMBO J 32:1990–2000
     [Google Scholar]
  13. 13. 
    Cohen I, Zhao D, Bar C, Valdes VJ, Dauber-Decker KL et al. 2018. PRC1 fine-tunes gene repression and activation to safeguard skin development and stem cell specification. Cell Stem Cell 22:726–39.e7
     [Google Scholar]
  14. 14. 
    Xiao Y, Thoresen DT, Miao L, Williams JS, Wang C et al. 2016. A cascade of Wnt, Eda, and Shh signaling is essential for touch dome Merkel cell development. PLOS Genet 12:e1006150
     [Google Scholar]
  15. 15. 
    Perdigoto CN, Dauber KL, Bar C, Tsai PC, Valdes VJ et al. 2016. Polycomb-mediated repression and Sonic hedgehog signaling interact to regulate Merkel cell specification during skin development. PLOS Genet 12:e1006151
     [Google Scholar]
  16. 16. 
    Jenkins BA, Fontecilla NM, Lu CP, Fuchs E, Lumpkin EA 2019. The cellular basis of mechanosensory Merkel-cell innervation during development. eLife 8:e42633
     [Google Scholar]
  17. 17. 
    Toker C. 1972. Trabecular carcinoma of the skin. Arch. Dermatol. 105:107–10
     [Google Scholar]
  18. 18. 
    Tang CK, Toker C. 1978. Trabecular carcinoma of the skin. An ultrastructural study. Cancer 42:2311–21
     [Google Scholar]
  19. 19. 
    Toker C. 1982. Trabecular carcinoma of the skin. A question of title. Am. J. Dermatopathol. 4:497–500
     [Google Scholar]
  20. 20. 
    Rywlin AM. 1982. Malignant Merkel-cell tumor is a more accurate description than trabecular carcinoma. Am. J. Dermatopathol. 4:513–15
     [Google Scholar]
  21. 21. 
    Lewis CW, Qazi J, Hippe DS, Lachance K, Thomas H et al. 2020. Patterns of distant metastases in 215 Merkel cell carcinoma patients: implications for prognosis and surveillance. Cancer Med 9:1374–82
     [Google Scholar]
  22. 22. 
    Stang A, Becker JC, Nghiem P, Ferlay J 2018. The association between geographic location and incidence of Merkel cell carcinoma in comparison to melanoma: an international assessment. Eur. J. Cancer 94:47–60
     [Google Scholar]
  23. 23. 
    Becker JC, Stang A, DeCaprio JA, Cerroni L, Lebbe C et al. 2017. Merkel cell carcinoma. Nat. Rev. Dis. Primers 3:17077
     [Google Scholar]
  24. 24. 
    Heath M, Jaimes N, Lemos B, Mostaghimi A, Wang LC et al. 2008. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J. Am. Acad. Dermatol. 58:375–81
     [Google Scholar]
  25. 25. 
    Harms KL, Healy MA, Nghiem P, Sober AJ, Johnson TM et al. 2016. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system. Ann. Surg. Oncol. 23:3564–71
     [Google Scholar]
  26. 26. 
    Trinidad CM, Torres-Cabala CA, Prieto VG, Aung PP 2019. Update on eighth edition American Joint Committee on Cancer classification for Merkel cell carcinoma and histopathological parameters that determine prognosis. J. Clin. Pathol. 72:337–40
     [Google Scholar]
  27. 27. 
    Iyer JG, Blom A, Doumani R, Lewis C, Tarabadkar ES et al. 2016. Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma. Cancer Med 5:2294–301
     [Google Scholar]
  28. 28. 
    Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ et al. 2016. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N. Engl. J. Med. 374:2542–52
     [Google Scholar]
  29. 29. 
    Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P et al. 2016. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17:1374–85
     [Google Scholar]
  30. 30. 
    D'Angelo SP, Russell J, Lebbe C, Chmielowski B, Gambichler T et al. 2018. Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma: a preplanned interim analysis of a clinical trial. JAMA Oncol 4:e180077
     [Google Scholar]
  31. 31. 
    Nghiem P, Bhatia S, Lipson EJ, Sharfman WH, Kudchadkar RR et al. 2019. Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy. J. Clin. Oncol. 37:693–702
     [Google Scholar]
  32. 32. 
    Leech SN, Kolar AJ, Barrett PD, Sinclair SA, Leonard N 2001. Merkel cell carcinoma can be distinguished from metastatic small cell carcinoma using antibodies to cytokeratin 20 and thyroid transcription factor 1. J. Clin. Pathol. 54:727–29
     [Google Scholar]
  33. 33. 
    Narisawa Y, Koba S, Inoue T, Nagase K 2015. Histogenesis of pure and combined Merkel cell carcinomas: an immunohistochemical study of 14 cases. J. Dermatol. 42:445–52
     [Google Scholar]
  34. 34. 
    Kervarrec T, Samimi M, Gaboriaud P, Gheit T, Beby-Defaux A et al. 2018. Detection of the Merkel cell polyomavirus in the neuroendocrine component of combined Merkel cell carcinoma. Virchows Arch 472:825–37
     [Google Scholar]
  35. 35. 
    Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW 2002. Merkel cell carcinoma and HIV infection. Lancet 359:497–98
     [Google Scholar]
  36. 36. 
    Clarke CA, Robbins HA, Tatalovich Z, Lynch CF, Pawlish KS et al. 2015. Risk of Merkel cell carcinoma after solid organ transplantation. J. Natl. Cancer Inst. 107:2dju382
     [Google Scholar]
  37. 37. 
    Feng H, Shuda M, Chang Y, Moore PS 2008. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096–100The discovery of Merkel cell polyomavirus in MCC demonstrates clonal viral DNA integration by southern blotting.
     [Google Scholar]
  38. 38. 
    Harms PW, Vats P, Verhaegen ME, Robinson DR, Wu YM et al. 2015. The distinctive mutational spectra of polyomavirus-negative Merkel cell carcinoma. Cancer Res 75:3720–27Along with Reference 39, demonstration of UV mutational signature in MCCN and lower mutational burden in MCCP.
     [Google Scholar]
  39. 39. 
    Goh G, Walradt T, Markarov V, Blom A, Riaz N et al. 2016. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 7:3403–15
     [Google Scholar]
  40. 40. 
    Gonzalez-Vela MDC, Curiel-Olmo S, Derdak S, Beltran S, Santibanez M et al. 2017. Shared oncogenic pathways implicated in both virus-positive and UV-induced Merkel cell carcinomas. J. Investig. Dermatol. 137:197–206
     [Google Scholar]
  41. 41. 
    Knepper TC, Montesion M, Russell JS, Sokol ES, Frampton GM et al. 2019. The genomic landscape of Merkel cell carcinoma and clinicogenomic biomarkers of response to immune checkpoint inhibitor therapy. Clin. Cancer Res. 25:5961–71
     [Google Scholar]
  42. 42. 
    Starrett GJ, Marcelus C, Cantalupo PG, Katz JP, Cheng J et al. 2017. Merkel cell polyomavirus exhibits dominant control of the tumor genome and transcriptome in virus-associated Merkel cell carcinoma. mBio 8:1e02079–16
     [Google Scholar]
  43. 43. 
    Starrett GJ, Thakuria M, Chen T, Marcelus C, Cheng J et al. 2020. Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma. Genome Med 12:30
     [Google Scholar]
  44. 44. 
    Houben R, Dreher C, Angermeyer S, Borst A, Utikal J et al. 2013. Mechanisms of p53 restriction in Merkel cell carcinoma cells are independent of the Merkel cell polyoma virus T antigens. J. Investig. Dermatol. 133:2453–60
     [Google Scholar]
  45. 45. 
    Hesbacher S, Pfitzer L, Wiedorfer K, Angermeyer S, Borst A et al. 2016. RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells. Oncotarget 7:32956–68
     [Google Scholar]
  46. 46. 
    Hafner C, Houben R, Baeurle A, Ritter C, Schrama D et al. 2012. Activation of the PI3K/AKT pathway in Merkel cell carcinoma. PLOS ONE 7:e31255
     [Google Scholar]
  47. 47. 
    Paulson KG, Lemos BD, Feng B, Jaimes N, Penas PF et al. 2009. Array-CGH reveals recurrent genomic changes in Merkel cell carcinoma including amplification of L-Myc. J. Investig. Dermatol. 129:1547–55
     [Google Scholar]
  48. 48. 
    Nau MM, Brooks BJ, Battey J, Sausville E, Gazdar AF et al. 1985. L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. Nature 318:69–73
     [Google Scholar]
  49. 49. 
    Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D et al. 2012. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat. Genet. 44:1104–10
     [Google Scholar]
  50. 50. 
    Hatton KS, Mahon K, Chin L, Chiu FC, Lee HW et al. 1996. Expression and activity of L-Myc in normal mouse development. Mol. Cell. Biol. 16:1794–804
     [Google Scholar]
  51. 51. 
    Wumesh KC, Satpathy AT, Rapaport AS, Briseno CG, Wu X et al. 2014. L-Myc expression by dendritic cells is required for optimal T-cell priming. Nature 507:243–47
     [Google Scholar]
  52. 52. 
    Anderson DA III, Murphy TL, Eisenman RN, Murphy KM 2020. The MYCL and MXD1 transcription factors regulate the fitness of murine dendritic cells. PNAS 117:4885–93
     [Google Scholar]
  53. 53. 
    Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB 2010. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe 7:509–15
     [Google Scholar]
  54. 54. 
    Ho J, Jedrych JJ, Feng H, Natalie AA, Grandinetti L et al. 2015. Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients. J. Infect. Dis. 211:1560–65
     [Google Scholar]
  55. 55. 
    Nguyen KD, Lee EE, Yue Y, Stork J, Pock L et al. 2017. Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses. J. Am. Acad. Dermatol. 76:932–40.e3
     [Google Scholar]
  56. 56. 
    van der Meijden E, Janssens RW, Lauber C, Bouwes Bavinck JN, Gorbalenya AE, Feltkamp MC 2010. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. PLOS Pathog 6:e1001024
     [Google Scholar]
  57. 57. 
    Nemeth K, Gorog A, Mezey E, Pinter D, Kuroli E et al. 2016. Cover image: Detection of hair follicle-associated Merkel cell polyomavirus in an immunocompromised host with follicular spicules and alopecia. Br. J. Dermatol. 175:1409
     [Google Scholar]
  58. 58. 
    Wu KN, McCue PA, Berger A, Spiegel JR, Wang ZX, Witkiewicz AK 2010. Detection of Merkel cell carcinoma polyomavirus in mucosal Merkel cell carcinoma. Int. J. Surg. Pathol. 18:342–46
     [Google Scholar]
  59. 59. 
    Lewis JS Jr., Duncavage E, Klonowski PW. 2010. Oral cavity neuroendocrine carcinoma: a comparison study with cutaneous Merkel cell carcinoma and other mucosal head and neck neuroendocrine carcinomas. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 110:209–17
     [Google Scholar]
  60. 60. 
    Carter JJ, Daugherty MD, Qi X, Bheda-Malge A, Wipf GC et al. 2013. Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes. PNAS 110:12744–49
     [Google Scholar]
  61. 61. 
    Hurdiss DL, Morgan EL, Thompson RF, Prescott EL, Panou MM et al. 2016. New structural insights into the genome and minor capsid proteins of BK polyomavirus using cryo-electron microscopy. Structure 24:528–36
     [Google Scholar]
  62. 62. 
    Chromy LR, Pipas JM, Garcea RL 2003. Chaperone-mediated in vitro assembly of Polyomavirus capsids. PNAS 100:10477–82
     [Google Scholar]
  63. 63. 
    Norkiene M, Stonyte J, Ziogiene D, Mazeike E, Sasnauskas K, Gedvilaite A 2015. Production of recombinant VP1-derived virus-like particles from novel human polyomaviruses in yeast. BMC Biotechnol 15:68
     [Google Scholar]
  64. 64. 
    Kean JM, Rao S, Wang M, Garcea RL 2009. Seroepidemiology of human polyomaviruses. PLOS Pathog 5:e1000363
     [Google Scholar]
  65. 65. 
    Trusch F, Klein M, Finsterbusch T, Kuhn J, Hofmann J, Ehlers B 2012. Seroprevalence of human polyomavirus 9 and cross-reactivity to African green monkey-derived lymphotropic polyomavirus. J. Gen. Virol. 93:698–705
     [Google Scholar]
  66. 66. 
    Faust H, Pastrana DV, Buck CB, Dillner J, Ekstrom J 2011. Antibodies to Merkel cell polyomavirus correlate to presence of viral DNA in the skin. J. Infect. Dis. 203:1096–100
     [Google Scholar]
  67. 67. 
    Paulson KG, Lewis CW, Redman MW, Simonson WT, Lisberg A et al. 2017. Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: a prospective validation study. Cancer 123:1464–74
     [Google Scholar]
  68. 68. 
    Pastrana DV, Tolstov YL, Becker JC, Moore PS, Chang Y, Buck CB 2009. Quantitation of human seroresponsiveness to Merkel cell polyomavirus. PLOS Pathog 5:e1000578
     [Google Scholar]
  69. 69. 
    Schrama D, Sarosi EM, Adam C, Ritter C, Kaemmerer U et al. 2019. Characterization of six Merkel cell polyomavirus-positive Merkel cell carcinoma cell lines: Integration pattern suggest that large T antigen truncating events occur before or during integration. Int. J. Cancer 145:1020–32
     [Google Scholar]
  70. 70. 
    Shuda M, Feng H, Kwun HJ, Rosen ST, Gjoerup O et al. 2008. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. PNAS 105:16272–77Characterization of truncated LT with loss of viral origin replication.
     [Google Scholar]
  71. 71. 
    Cheng J, Rozenblatt-Rosen O, Paulson KG, Nghiem P, DeCaprio JA 2013. Merkel cell polyomavirus large T antigen has growth-promoting and inhibitory activities. J. Virol. 87:6118–26
     [Google Scholar]
  72. 72. 
    Li J, Wang X, Diaz J, Tsang SH, Buck CB, You J 2013. Merkel cell polyomavirus large T antigen disrupts host genomic integrity and inhibits cellular proliferation. J. Virol. 87:9173–88
     [Google Scholar]
  73. 73. 
    Schrama D, Hesbacher S, Angermeyer S, Schlosser A, Haferkamp S et al. 2016. Serine 220 phosphorylation of the Merkel cell polyomavirus large T antigen crucially supports growth of Merkel cell carcinoma cells. Int. J. Cancer 138:1153–62
     [Google Scholar]
  74. 74. 
    Houben R, Angermeyer S, Haferkamp S, Aue A, Goebeler M et al. 2015. Characterization of functional domains in the Merkel cell polyoma virus Large T antigen. Int. J. Cancer 136:E290–300
     [Google Scholar]
  75. 75. 
    Park DE, Cheng J, Berrios C, Montero J, Cortes-Cros M et al. 2019. Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response. PNAS 116:1027–32
     [Google Scholar]
  76. 76. 
    Czech-Sioli M, Siebels S, Radau S, Zahedi RP, Schmidt C et al. 2020. The ubiquitin specific protease Usp7, a novel Merkel cell polyomavirus large T-antigen interaction partner, modulates viral DNA replication. J. Virol. 94:5e01638–19
     [Google Scholar]
  77. 77. 
    Wang X, Li J, Schowalter RM, Jiao J, Buck CB, You J 2012. Bromodomain protein Brd4 plays a key role in Merkel cell polyomavirus DNA replication. PLOS Pathog 8:e1003021
     [Google Scholar]
  78. 78. 
    Feng H, Kwun HJ, Liu X, Gjoerup O, Stolz DB et al. 2011. Cellular and viral factors regulating Merkel cell polyomavirus replication. PLOS ONE 6:e22468
     [Google Scholar]
  79. 79. 
    Liu X, Hein J, Richardson SC, Basse PH, Toptan T et al. 2011. Merkel cell polyomavirus large T antigen disrupts lysosome clustering by translocating human Vam6p from the cytoplasm to the nucleus. J. Biol. Chem. 286:17079–90
     [Google Scholar]
  80. 80. 
    Kwun HJ, Chang Y, Moore PS 2017. Protein-mediated viral latency is a novel mechanism for Merkel cell polyomavirus persistence. PNAS 114:E4040–47
     [Google Scholar]
  81. 81. 
    Dye KN, Welcker M, Clurman BE, Roman A, Galloway DA 2019. Merkel cell polyomavirus Tumor antigens expressed in Merkel cell carcinoma function independently of the ubiquitin ligases Fbw7 and β-TrCP. PLOS Pathog 15:e1007543
     [Google Scholar]
  82. 82. 
    Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K et al. 2014. Merkel cell polyomavirus (MCPyV) strains in Japanese merkel cell carcinomas (MCC) are distinct from Caucasian type MCPyVs: genetic variability and phylogeny of MCPyV genomes obtained from Japanese MCPyV-infected MCCs. Virus Genes 48:233–42
     [Google Scholar]
  83. 83. 
    Borchert S, Czech-Sioli M, Neumann F, Schmidt C, Wimmer P et al. 2014. High-affinity Rb binding, p53 inhibition, subcellular localization, and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens. J. Virol. 88:3144–60
     [Google Scholar]
  84. 84. 
    Siebels S, Czech-Sioli M, Spohn M, Schmidt C, Theiss J et al. 2020. Merkel cell polyomavirus DNA replication induces senescence in human dermal fibroblasts in a Kap1/Trim28-dependent manner. mBio 11:2e00142–20
     [Google Scholar]
  85. 85. 
    Schaffhausen BS, Roberts TM. 2009. Lessons from polyoma middle T antigen on signaling and transformation: a DNA tumor virus contribution to the war on cancer. Virology 384:304–16
     [Google Scholar]
  86. 86. 
    Shuda M, Kwun HJ, Feng H, Chang Y, Moore PS 2011. Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. J. Clin. Investig. 121:3623–34
     [Google Scholar]
  87. 87. 
    Verhaegen ME, Mangelberger D, Harms PW, Eberl M, Wilbert DM et al. 2017. Merkel cell polyomavirus small T antigen initiates Merkel cell carcinoma-like tumor development in mice. Cancer Res 77:3151–57
     [Google Scholar]
  88. 88. 
    Cho US, Morrone S, Sablina AA, Arroyo JD, Hahn WC, Xu W 2007. Structural basis of PP2A inhibition by small t antigen. PLOS Biol 5:e202
     [Google Scholar]
  89. 89. 
    Chen Y, Xu Y, Bao Q, Xing Y, Li Z et al. 2007. Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40. Nat. Struct. Mol. Biol. 14:527–34
     [Google Scholar]
  90. 90. 
    Pallas DC, Shahrik LK, Martin BL, Jaspers S, Miller TB et al. 1990. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 60:167–76
     [Google Scholar]
  91. 91. 
    Kwun HJ, Shuda M, Camacho CJ, Gamper AM, Thant M et al. 2015. Restricted protein phosphatase 2A targeting by Merkel cell polyomavirus small T antigen. J. Virol. 89:4191–200
     [Google Scholar]
  92. 92. 
    Cheng J, Park DE, Berrios C, White EA, Arora R et al. 2017. Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis. PLOS Pathog 13:e1006668Identification of the MCPyV ST antigen, MYCL/MAX, and EP400 complex and downstream gene activation.
     [Google Scholar]
  93. 93. 
    Chen W, Possemato R, Campbell KT, Plattner CA, Pallas DC, Hahn WC 2004. Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 5:127–36
     [Google Scholar]
  94. 94. 
    Andrabi S, Hwang JH, Choe JK, Roberts TM, Schaffhausen BS 2011. Comparisons between murine polyomavirus and Simian virus 40 show significant differences in small T antigen function. J. Virol. 85:10649–58
     [Google Scholar]
  95. 95. 
    Kim JW, Berrios C, Kim M, Schade AE, Adelmant G et al. 2020. STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells. eLife 9:e53003
     [Google Scholar]
  96. 96. 
    Park J, Wood MA, Cole MD 2002. BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation. Mol. Cell. Biol. 22:1307–16
     [Google Scholar]
  97. 97. 
    Frank SR, Parisi T, Taubert S, Fernandez P, Fuchs M et al. 2003. MYC recruits the TIP60 histone acetyltransferase complex to chromatin. EMBO Rep 4:575–80
     [Google Scholar]
  98. 98. 
    Kim J, Woo AJ, Chu J, Snow JW, Fujiwara Y et al. 2010. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143:313–24
     [Google Scholar]
  99. 99. 
    Kalkat M, Resetca D, Lourenco C, Chan PK, Wei Y et al. 2018. MYC protein interactome profiling reveals functionally distinct regions that cooperate to drive tumorigenesis. Mol. Cell 72:836–48.e7
     [Google Scholar]
  100. 100. 
    Slack A, Chen Z, Tonelli R, Pule M, Hunt L et al. 2005. The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. PNAS 102:731–36
     [Google Scholar]
  101. 101. 
    Gamble LD, Kees UR, Tweddle DA, Lunec J 2012. MYCN sensitizes neuroblastoma to the MDM2-p53 antagonists Nutlin-3 and MI-63. Oncogene 31:752–63
     [Google Scholar]
  102. 102. 
    Chen L, Iraci N, Gherardi S, Gamble LD, Wood KM et al. 2010. p53 is a direct transcriptional target of MYCN in neuroblastoma. Cancer Res 70:1377–88
     [Google Scholar]
  103. 103. 
    Knight LM, Stakaityte G, Wood JJ, Abdul-Sada H, Griffiths DA et al. 2015. Merkel cell polyomavirus small T antigen mediates microtubule destabilization to promote cell motility and migration. J. Virol. 89:35–47
     [Google Scholar]
  104. 104. 
    Stakaityte G, Nwogu N, Dobson SJ, Knight LM, Wasson CW et al. 2018. Merkel cell polyomavirus small T antigen drives cell motility via Rho-GTPase-induced filopodium formation. J. Virol. 92:2e00940–17
     [Google Scholar]
  105. 105. 
    Grimes HL, Chan TO, Zweidler-McKay PA, Tong B, Tsichlis PN 1996. The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal. Mol. Cell. Biol. 16:6263–72
     [Google Scholar]
  106. 106. 
    Velinder M, Singer J, Bareyan D, Meznarich J, Tracy CM et al. 2016. GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1. Biochem. J. 473:3355–69
     [Google Scholar]
  107. 107. 
    Maiques-Diaz A, Spencer GJ, Lynch JT, Ciceri F, Williams EL et al. 2018. Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia. Cell Rep 22:3641–59
     [Google Scholar]
  108. 108. 
    Takagi S, Ishikawa Y, Mizutani A, Iwasaki S, Matsumoto S et al. 2017. LSD1 inhibitor T-3775440 inhibits SCLC cell proliferation by disrupting LSD1 interactions with SNAG domain proteins INSM1 and GFI1B. Cancer Res 77:4652–62
     [Google Scholar]
  109. 109. 
    Park DE, Cheng J, McGrath JP, Lim MY, Cushman C et al. 2020. Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis. Nat. Cell Biol. 22:603–15The LSD1-RCOR2-INSM1 complex represses ATOH1-dependent gene expression.
     [Google Scholar]
  110. 110. 
    Fan K, Gravemeyer J, Ritter C, Rasheed K, Gambichler T et al. 2020. MCPyV large T antigen-induced atonal homolog 1 is a lineage-dependency oncogene in Merkel cell carcinoma. J. Investig. Dermatol. 140:56–65.e3Overexpression of ATOH1 promotes neuroendocrine differentiation in MCCN cell lines.
     [Google Scholar]
  111. 111. 
    Gambichler T, Mohtezebsade S, Wieland U, Silling S, Hoh AK et al. 2017. Prognostic relevance of high atonal homolog-1 expression in Merkel cell carcinoma. J. Cancer Res. Clin. Oncol. 143:43–49
     [Google Scholar]
  112. 112. 
    Kuromi T, Matsushita M, Iwasaki T, Nonaka D, Kuwamoto S et al. 2017. Association of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma. Hum. Pathol. 69:8–14
     [Google Scholar]
  113. 113. 
    Harms KL, Chubb H, Zhao L, Fullen DR, Bichakjian CK et al. 2017. Increased expression of EZH2 in Merkel cell carcinoma is associated with disease progression and poorer prognosis. Hum. Pathol. 67:78–84
     [Google Scholar]
  114. 114. 
    Burr ML, Sparbier CE, Chan KL, Chan YC, Kersbergen A et al. 2019. An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell 36:385–401.e8
     [Google Scholar]
  115. 115. 
    Paulson KG, Tegeder A, Willmes C, Iyer JG, Afanasiev OK et al. 2014. Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma. Cancer Immunol. Res. 2:1071–79
     [Google Scholar]
  116. 116. 
    Ritter C, Fan K, Paulson KG, Nghiem P, Schrama D, Becker JC 2016. Reversal of epigenetic silencing of MHC class I chain-related protein A and B improves immune recognition of Merkel cell carcinoma. Sci. Rep. 6:21678
     [Google Scholar]
  117. 117. 
    Ugurel S, Spassova I, Wohlfarth J, Drusio C, Cherouny A et al. 2019. MHC class-I downregulation in PD-1/PD-L1 inhibitor refractory Merkel cell carcinoma and its potential reversal by histone deacetylase inhibition: a case series. Cancer Immunol. Immunother. 68:983–90
     [Google Scholar]
  118. 118. 
    Busam KJ, Jungbluth AA, Rekthman N, Coit D, Pulitzer M et al. 2009. Merkel cell polyomavirus expression in Merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am. J. Surg. Pathol. 33:1378–85
     [Google Scholar]
  119. 119. 
    Narisawa Y, Inoue T, Nagase K 2019. Evidence of proliferative activity in human Merkel cells: implications in the histogenesis of Merkel cell carcinoma. Arch. Dermatol. Res. 311:37–43
     [Google Scholar]
  120. 120. 
    Spurgeon ME, Cheng J, Bronson RT, Lambert PF, DeCaprio JA 2015. Tumorigenic activity of Merkel cell polyomavirus T antigens expressed in the stratified epithelium of mice. Cancer Res 75:1068–79
     [Google Scholar]
  121. 121. 
    Shuda M, Guastafierro A, Geng X, Shuda Y, Ostrowski SM et al. 2015. Merkel cell polyomavirus small T antigen induces cancer and embryonic Merkel cell proliferation in a transgenic mouse model. PLOS ONE 10:e0142329
     [Google Scholar]
  122. 122. 
    Verhaegen ME, Mangelberger D, Harms PW, Vozheiko TD, Weick JW et al. 2015. Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice. J. Investig. Dermatol. 135:1415–24
     [Google Scholar]
  123. 123. 
    Misago N, Satoh T, Miura Y, Nagase K, Narisawa Y 2007. Merkel cell-poor trichoblastoma with basal cell carcinoma-like foci. Am. J. Dermatopathol. 29:249–55
     [Google Scholar]
  124. 124. 
    Kervarrec T, Aljundi M, Appenzeller S, Samimi M, Maubec E et al. 2019. Polyomavirus-positive Merkel cell carcinoma derived from a trichoblastoma suggests an epithelial origin of this Merkel cell carcinoma. J. Investig. Dermatol. 140:5976–85
     [Google Scholar]
  125. 125. 
    zur Hausen A, Rennspiess D, Winnepenninckx V, Speel EJ, Kurz AK 2013. Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry. Cancer Res 73:4982–87
     [Google Scholar]
  126. 126. 
    Kervarrec T, Samimi M, Guyetant S, Sarma B, Cheret J et al. 2019. Histogenesis of Merkel cell carcinoma: a comprehensive review. Front. Oncol. 9:451
     [Google Scholar]
  127. 127. 
    Liu W, Yang R, Payne AS, Schowalter RM, Spurgeon ME et al. 2016. Identifying the target cells and mechanisms of Merkel cell polyomavirus infection. Cell Host Microbe 19:775–87
     [Google Scholar]
  128. 128. 
    Kraft S, Granter SR. 2014. Molecular pathology of skin neoplasms of the head and neck. Arch. Pathol. Lab. Med. 138:759–87
     [Google Scholar]
/content/journals/10.1146/annurev-pathmechdis-012419-032817
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Molecular Pathogenesis of Merkel Cell Carcinoma
Annual Review of Pathology: Mechanisms of Disease 16, 69 (2021); https://doi.org/10.1146/annurev-pathmechdis-012419-032817
/content/journals/10.1146/annurev-pathmechdis-012419-032817
/content/journals/10.1146/annurev-pathmechdis-012419-032817
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