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Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice

Monique E. Verhaegen, Doris Mangelberger, Paul W. Harms, Markus Eberl, Dawn M. Wilbert, Julia Meireles, Christopher K. Bichakjian, Thomas L. Saunders, Sunny Y. Wong and Andrzej A. Dlugosz
Monique E. Verhaegen
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
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Doris Mangelberger
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
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Paul W. Harms
Department of Pathology, University of Michigan, Ann Arbor, Michigan.
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Markus Eberl
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
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Dawn M. Wilbert
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
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Julia Meireles
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
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Christopher K. Bichakjian
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
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Thomas L. Saunders
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Sunny Y. Wong
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan.
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Andrzej A. Dlugosz
Department of Dermatology, University of Michigan, Ann Arbor, Michigan.Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan.
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  • For correspondence: dlugosza@umich.edu
DOI: 10.1158/0008-5472.CAN-17-0035 Published June 2017
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Abstract

Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a nonproliferative population of neuroendocrine cells that arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of preterm transgenic mice, we show that epidermis-targeted coexpression of sT and the cell fate-determinant atonal bHLH transcription factor 1 (ATOH1) leads to development of widespread cellular aggregates, with histology and marker expression mimicking that of human intraepidermal MCC. The MCC-like tumor phenotype was dependent on the FBXW7-binding domain of sT, but not the sT-PP2A binding domain. Coexpression of MCPyV tLT did not appreciably alter the phenotype driven by either sT or sT combined with ATOH1. MCPyV sT, when coexpressed with ATOH1, is thus sufficient to initiate development of epidermis-derived MCC-like tumors in mice. Cancer Res; 77(12); 3151–7. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received January 4, 2017.
  • Revision received January 17, 2017.
  • Accepted April 19, 2017.
  • ©2017 American Association for Cancer Research.
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Cancer Research: 77 (12)
June 2017
Volume 77, Issue 12
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Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice
Monique E. Verhaegen, Doris Mangelberger, Paul W. Harms, Markus Eberl, Dawn M. Wilbert, Julia Meireles, Christopher K. Bichakjian, Thomas L. Saunders, Sunny Y. Wong and Andrzej A. Dlugosz
Cancer Res June 15 2017 (77) (12) 3151-3157; DOI: 10.1158/0008-5472.CAN-17-0035

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Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice
Monique E. Verhaegen, Doris Mangelberger, Paul W. Harms, Markus Eberl, Dawn M. Wilbert, Julia Meireles, Christopher K. Bichakjian, Thomas L. Saunders, Sunny Y. Wong and Andrzej A. Dlugosz
Cancer Res June 15 2017 (77) (12) 3151-3157; DOI: 10.1158/0008-5472.CAN-17-0035
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