Journal Article

Cellular sheddases are induced by Merkel cell polyomavirus small tumour antigen to mediate cell dissociation and invasiveness

Blair, G. Eric, Boyne, James R., Macdonald, Andrew, Poterlowicz, Krzysztof, Dobson, Samuel J., Mankouri, Jamel, Whitehouse, Adrian, Nwogu, Nnenna

2018

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ADAM protein / ADAM10 Protein - metabolism / ADAM17 Protein - metabolism / Amyloid Precursor Protein Secretases - metabolism / Antigens / Antigens, Viral, Tumor - physiology / Biology and Life Sciences / Biomarkers / Cancer / Carcinoma, Merkel Cell - enzymology / Carcinoma, Merkel Cell - etiology / Carcinoma, Merkel Cell - secondary / Causes of / Cell adhesion & migration / Cell cycle / Cell junctions / Cell Movement / Cellular biology / Development and progression / Extracellular matrix / Gene expression / Genetic aspects / Genomes / HEK293 Cells / Humans / Intercellular Junctions - pathology / Intercellular Junctions - physiology / Invasiveness / Kinases / Life sciences / Medicine and Health Sciences / Membrane Proteins - metabolism / Merkel cell carcinoma / Merkel cell polyomavirus - immunology / Merkel cell polyomavirus - pathogenicity / Merkel cell polyomavirus - physiology / Metastases / Metastasis / Molecular biology / Motility / Neoplasm Invasiveness - pathology / Neoplasm Invasiveness - physiopathology / Physiological aspects / Polyoma virus / Polyomavirus / Polyomavirus Infections - enzymology / Polyomavirus Infections - etiology / Polyomavirus Infections - pathology / Proteins / Research and analysis methods / Skin cancer / Skin Neoplasms - enzymology / Skin Neoplasms - etiology / Skin Neoplasms - pathology / Transformation / Tumor Virus Infections - enzymology / Tumor Virus Infections - etiology / Tumor Virus Infections - pathology / Tumors / Viruses