Direct cellular reprogramming enables development of viral T antigen–driven Merkel cell carcinoma in mice
Monique E. Verhaegen, … , Lam C. Tsoi, Andrzej A. Dlugosz
Monique E. Verhaegen, … , Lam C. Tsoi, Andrzej A. Dlugosz
Published February 10, 2022
Citation Information: J Clin Invest. 2022;132(7):e152069. https://doi.org/10.1172/JCI152069.
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Concise Communication Dermatology Oncology

Direct cellular reprogramming enables development of viral T antigen–driven Merkel cell carcinoma in mice

Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that frequently carries an integrated Merkel cell polyomavirus (MCPyV) genome and expresses viral transforming antigens (TAgs). MCC tumor cells also express signature genes detected in skin-resident, postmitotic Merkel cells, including atonal bHLH transcription factor 1 (ATOH1), which is required for Merkel cell development from epidermal progenitors. We now report the use of in vivo cellular reprogramming, using ATOH1, to drive MCC development from murine epidermis. We generated mice that conditionally expressed MCPyV TAgs and ATOH1 in epidermal cells, yielding microscopic collections of proliferating MCC-like cells arising from hair follicles. Immunostaining of these nascent tumors revealed p53 accumulation and apoptosis, and targeted deletion of transformation related protein 53 (Trp53) led to development of gross skin tumors with classic MCC histology and marker expression. Global transcriptome analysis confirmed the close similarity of mouse and human MCCs, and hierarchical clustering showed conserved upregulation of signature genes. Our data establish that expression of MCPyV TAgs in ATOH1-reprogrammed epidermal cells and their neuroendocrine progeny initiates hair follicle–derived MCC tumorigenesis in adult mice. Moreover, progression to full-blown MCC in this model requires loss of p53, mimicking the functional inhibition of p53 reported in human MCPyV-positive MCCs.

Authors

Monique E. Verhaegen, Paul W. Harms, Julia J. Van Goor, Jacob Arche, Matthew T. Patrick, Dawn Wilbert, Haley Zabawa, Marina Grachtchouk, Chia-Jen Liu, Kevin Hu, Michael C. Kelly, Ping Chen, Thomas L. Saunders, Stephan Weidinger, Li-Jyun Syu, John S. Runge, Johann E. Gudjonsson, Sunny Y. Wong, Isaac Brownell, Marcin Cieslik, Aaron M. Udager, Arul M. Chinnaiyan, Lam C. Tsoi, Andrzej A. Dlugosz

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Figure 2

In vivo reprogramming using ATOH1 in p53-deficient cells enables development of full-blown murine MCC.

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In vivo reprogramming using ATOH1 in p53-deficient cells enables develop...
(A) Addition of conditional Trp53 allele to generate SLAP mice expressing MCPyV sTAg, tLTAg, and ATOH1, which are also deficient in p53, in Krt5-expressing cells and their progeny. (B) Gross tumor arising in SLAP mouse 4 months after transgene induction. (C) Similar histopathology of SLAP mouse tumor and human MCC. Immunostaining for (D) transgene expression and (E) MCC marker expression. Scale bars: 25 μm.