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

• Type of Material: Article
• Authors: Monique E Verhaegen, University of Michigan; Paul W Harms, University of Michigan; Julia J Van Goor, University of Michigan; Jacob Arche, University of Michigan; Matthew T Patrick, University of Michigan; Dawn Wilbert, University of Michigan; Haley Zabawa, University of Michigan; Marina Grachtchouk, University of Michigan; Chia-Jen Liu, University of Michigan; Kevin Hu, University of Michigan; Michael C Kelly, Emory University; Ping Chen, Emory University; Thomas L Saunders, University of Michigan; Stephan Weidinger, Univ Med Ctr Schleswig Holstein; Li-Jyun Syu, University of Michigan; John S Runge, University of Michigan; Johann E Gudjonsson, University of Michigan; Sunny Y Wong, University of Michigan; Isaac Brownell, National Cancer Institute, Bethesda; Marcin Cieslik, University of Michigan; Aaron M Udager, University of Michigan; Arul M Chinnaiyan, University of Michigan; Lam C Tsoi, University of Michigan; Andrzej A Dlugosz, University of Michigan
• Language: English
• Date: 2022-04-01
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Verhaegen et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI152069
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 132
• Issue: 7
• Grant/Funding Information: This work was supported by a University of Michigan Rogel Cancer Center support grant (P30 CA046592), the University of Michigan Skin Biology and Diseases Resource-based Center (P30 AR075043), the University of Michigan Center for Gastrointestinal Research (P30 DK034933), the Leo Foundation (LF08017 to SYW), the American Cancer Society (RSG-18-065-01-TBG to SYW), and the National Cancer Institute (R01 CA189352 and CA241947 to AAD and MEV).
• Keywords: POLYOMAVIRUS; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; Science & Technology; LAYER
• Research Categories: Health Sciences, Pathology; Biology, Cell

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.