title: Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection.
abstract: Infection with Merkel cell polyomavirus (MCPyV) can lead to Merkel cell carcinoma (MCC), a lethal form of skin cancer. However, the skin cell type productively infected by MCPyV remains a central question. We combined cell culture and ex vivo approaches to identify human dermal fibroblasts as natural host cells that support productive MCPyV infection. Based on this, we established a cell culture model for MCPyV infection, which will facilitate investigation of the oncogenic mechanisms for this DNA virus. Using this model, we discovered that induction of matrix metalloproteinase (MMP) genes by the WNT/β-catenin signaling pathway and other growth factors stimulates MCPyV infection. This suggests that MCC risk factors such as UV radiation and aging, which are known to stimulate WNT signaling and MMP expression, may promote viral infection and thus drive MCC. Our study also introduces the FDA-approved MEK antagonist trametinib as an effective inhibitor for controlling MCPyV infection.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Aimee S
authors.initials: AS
authors.lastname: Payne
authors.affiliation: Tumor Virus Molecular Biology Section, Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Schowalter
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Spurgeon
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Tumor Virus Molecular Biology Section, Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Buck
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jianyou@mail.med.upenn.edu.
authors.forename: Jianxin
authors.initials: J
authors.lastname: You
mesh_terms: D000328:Adult; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005347:Fibroblasts / Q000473:pathology / Q000821:virology; D006801:Humans; D007223:Infant; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D059965:Merkel cell polyomavirus / Q000472:pathogenicity*; D027601:Polyomavirus Infections / Q000473:pathology / Q000821:virology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012307:Risk Factors; D015398:Signal Transduction; D012867:Skin / Q000473:pathology* / Q000821:virology*
chemical_list: D047428:Protein Kinase Inhibitors; D020782:Matrix Metalloproteinases