Date Published: September 6, 2018
Publisher: Public Library of Science
Author(s): Nnenna Nwogu, James R. Boyne, Samuel J. Dobson, Krzysztof Poterlowicz, G. Eric Blair, Andrew Macdonald, Jamel Mankouri, Adrian Whitehouse, Denise A. Galloway.
Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is recognised as the causative factor in the majority of MCC cases. The MCPyV small tumour antigen (ST) is considered to be the main viral transforming factor, however potential mechanisms linking ST expression to the highly metastatic nature of MCC are yet to be fully elucidated. Metastasis is a complex process, with several discrete steps required for the formation of secondary tumour sites. One essential trait that underpins the ability of cancer cells to metastasise is how they interact with adjoining tumour cells and the surrounding extracellular matrix. Here we demonstrate that MCPyV ST expression disrupts the integrity of cell-cell junctions, thereby enhancing cell dissociation and implicate the cellular sheddases, A disintegrin and metalloproteinase (ADAM) 10 and 17 proteins in this process. Inhibition of ADAM 10 and 17 activity reduced MCPyV ST-induced cell dissociation and motility, attributing their function as critical to the MCPyV-induced metastatic processes. Consistent with these data, we confirm that ADAM 10 and 17 are upregulated in MCPyV-positive primary MCC tumours. These novel findings implicate cellular sheddases as key host cell factors contributing to virus-mediated cellular transformation and metastasis. Notably, ADAM protein expression may be a novel biomarker of MCC prognosis and given the current interest in cellular sheddase inhibitors for cancer therapeutics, it highlights ADAM 10 and 17 activity as a novel opportunity for targeted interventions for disseminated MCC.
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine cancer of the skin . Although rare, the incidence of MCC has increased over the past twenty years in both Europe and the United States of America , attributed to advances in reporting, diagnostic improvements and known risk factors. UV light appears to be an important factor in MCC, with a positive correlation between geographic UVB radiation indices and age-adjusted MCC amongst Caucasians [1, 3]. The predominance of MCC in elderly persons also highlights immunosuppression as an important risk factor, supported by disproportionally higher rates of MCC in patients on long-term iatrogenic immunosuppression, in addition to patients with lymphoproliferative disorders and HIV/AIDs . Due to its aggressive nature MCC carries a high risk of local, regional and distant recurrence . As such, the 5-year survival rates range from 60–87% for local disease to 11–20% for metastatic disease [5–7].
MCPyV ST has emerged as the major transforming factor in MCPyV-positive MCC. Recently we reported a potential role for MCPyV ST in MCC metastasis, whereby ST cultivates a pro-migratory cell phenotype by destabilising microtubules , inducing filopodia formation  and modulating cellular chloride channels . Cancer metastasis occurs via a series of complex events that are collectively known as the invasion-metastasis cascade . The apex event in the metastatic cascade is broadly accepted to be mediated by an EMT, providing tumour cells increased motility allowing invasion of the ECM. Most oncoviruses have been shown to manipulate the EMT axis, for example, human papillomavirus 16, Epstein-Barr virus (EBV), hepatitis B virus and the polyomavirus simian virus 40 have all been shown to induce metastasis, through a variety of mechanisms including; cellular adhesion complexes, cytoskeletal reorganisation and gene expression modulation [62–65]. EBV latent membrane protein-1, for example orchestrates EMT via several different routes, including the transcriptional repression of E-cadherin via activation of DNA methyltransferases  and increased expression of the pleiotropic EMT transcription factors, Twist and Snail [67, 68].