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

February 16, 2022


The Journal of Clinical Investigation

Publication Date

February 16, 2022

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One of the issues most often raised in the field of Merkel cell carcinoma is ‘why is there no mouse model for this polymavirus-driven cancer?’ The study by Verhaegen and colleagues answers that question, after well over a decade of effort by over a dozen labs attempting to do this. Simply put, it was really hard.

There are obviously important ‘wiring differences’ between human and rodent cells that mean the OTHER polyomaviruses cause many cancers in mice, but not in humans (SV-40 is the best example), yet that the Merkel cell polyomavirus causes cancer in humans, but not in mice. This team has gone to extraordinary measures to identify the key components and overcome technical barriers to generate a mouse Merkel cell carcinoma that is driven by key oncoproteins from the Merkel virus.


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, post-mitotic Merkel cells, including 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 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.

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