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 integratedMerkel 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.

Milademetan is a highly potent MDM2 inhibitor in Merkel cell carcinoma

“…One such ST-MYCL-EP400 target gene is MDM2, the negative regulator of p53 ( 8 , 9 , 20 , 28 , 29 ). Functional inactivation of human p53 protein in MCCP tumors or murine Trp53 deletion in MCCP mouse models is required to generate a MCC phenotype ( 30 ). Thus, restoring p53 function in MCCP tumors could be a beneficial antitumor strategy.…”

Merkel cell polyomavirus large T antigen binding to pRb promotes skin hyperplasia and tumor development

“…Moreover, co-expression of ST and Atoh1 in the epithelium was sufficient to facilitate the development of intraepidermal MCC-like lesions in murine skin [ 36 ]. More recently, a murine model was reported in which full-blown MCC tumors developed in the skin of mice expressing MCPyV truncated LT and ST together with Atoh1 expression and loss of p53 [ 35 ]. Epithelial-specific expression of ST alone also induced many of the same phenotypes we have observed in K14Cre-MCPyV168 mice expressing ST and LT in the stratified squamous epithelium, including hyperplasia, increased proliferation, and activation of the DNA damage response [ 31 , 36 , 37 , 52 ].…”

“…In MCC cell lines, ST can specifically recruit MYCL and MAX to the EP400 complex to transactivate a large number of genes that contribute to its transforming functions [ 34 ]. MCPyV ST, alone, has also been shown to be tumorigenic in transgenic mouse models [ 31 , 35 – 37 ] and promotes the development of intra-epidermal MCC-like lesions when expressed together with the Merkel cell specification factor atonal homolog 1 (Atoh1) in epithelial cells [ 36 ]. More recently, Verhaegen and colleagues have demonstrated the development of MCC with striking phenotypic and molecular similarities to human MCC in mice expressing MCPyV LT and ST together with Atoh1 on a p53-deficient background [ 35 ].…”

“…MCPyV ST, alone, has also been shown to be tumorigenic in transgenic mouse models [ 31 , 35 – 37 ] and promotes the development of intra-epidermal MCC-like lesions when expressed together with the Merkel cell specification factor atonal homolog 1 (Atoh1) in epithelial cells [ 36 ]. More recently, Verhaegen and colleagues have demonstrated the development of MCC with striking phenotypic and molecular similarities to human MCC in mice expressing MCPyV LT and ST together with Atoh1 on a p53-deficient background [ 35 ]. On the other hand, evidence for a robust transforming activity of MCPyV LT has not yet been demonstrated [ 25 , 30 ].…”

Small DNA tumor viruses and human cancer: Preclinical models of virus infection and disease

“…More recently, the first transgenic mouse model of MCC development was reported [ 303 ]. For this model, Verhaegen and colleagues employed various inducible and conditional transgene targeting strategies to achieve tightly controlled tissue-specific expression of the MCPyV T antigens, Atoh1, and p53 deficiency in the skin.…”