title: Spontaneous lung metastasis formation of human Merkel cell carcinoma cell lines transplanted into scid mice.
abstract: Merkel cell carcinoma (MCC) is an aggressive skin cancer entity that frequently leads to rapid death due to its high propensity to metastasize. The etiology of most MCC cases is linked to Merkel cell polyomavirus (MCPyV), a virus which is monoclonally integrated in up to 95% of tumors. While there are presently no animal models to study the role of authentic MCPyV infection on transformation, tumorigenesis or metastasis formation, xenograft mouse models employing engrafted MCC-derived cell lines (MCCL) represent a promising approach to study certain aspects of MCC pathogenesis. Here, the two MCPyV-positive MCC cell lines WaGa and MKL-1 were subcutaneously engrafted in scid mice. Engraftment of both MCC cell lines resulted in the appearance of circulating tumor cells and metastasis formation, with WaGa-engrafted mice showing a significantly shorter survival time as well as increased numbers of spontaneous lung metastases compared to MKL-1 mice. Interestingly, explanted tumors compared to parental cell lines exhibit an upregulation of MCPyV sT-Antigen expression in all tumors, with WaGa tumors showing significantly higher sT-Antigen expression than MKL-1 tumors. RNA-Seq analysis of explanted tumors and parental cell lines furthermore revealed that in the more aggressive WaGa tumors, genes involved in inflammatory response, growth factor activity and Wnt signalling pathway are significantly upregulated, suggesting that sT-Antigen is the driver of the observed differences in metastasis formation.
authors.affiliation: Institute of Anatomy and Experimental Morphology, University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jill
authors.initials: J
authors.lastname: Knips
authors.affiliation: Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Research Group Virus Genomics, Hamburg, Germany.
authors.forename: Manja
authors.initials: M
authors.lastname: Czech-Sioli
authors.affiliation: Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Research Group Virus Genomics, Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Spohn
authors.affiliation: Department of Oral and Maxillofacial Surgery, Charité Universitätsmedizin Berlin, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Heiland
authors.affiliation: Department of Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Moll
authors.affiliation: Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Research Group Virus Genomics, Hamburg, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Grundhoff
authors.affiliation: Institute of Anatomy and Experimental Morphology, University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.affiliation: Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nicole
authors.identifier: 0000-0002-5092-8179
authors.initials: N
authors.lastname: Fischer
mesh_terms: D000818:Animals; D015266:Carcinoma, Merkel Cell / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary / Q000821:virology*; D059965:Merkel cell polyomavirus / Q000472:pathogenicity*; D051379:Mice; D009362:Neoplasm Metastasis; D027601:Polyomavirus Infections / Q000473:pathology / Q000821:virology*; D014412:Tumor Virus Infections / Q000473:pathology / Q000821:virology*; D023041:Xenograft Model Antitumor Assays
keywords: Merkel cell cancer; Merkel cell polyomavirus; metastasis formation; transcriptome analysis; xenograft scid mouse