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

Abstract

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 Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

“…Recent studies have highlighted the involvement of MCV sT in the highly migratory and cell dissociation phenotypes of MCC, elucidating its highly multifunctional roles in MCC (16–18). Previously described SILAC (stable isotope labelling by amino acids in cell culture)-based quantitative proteomics data (REF), was further interrogated to assess the alterations in the host cell proteome upon expression of MCV sT in a HEK293 derived cell line (i293-sT) (Fig.…”

“…2A). (16–18, 40, 41). Interestingly, sT mutant, sT LSDm , showed a decrease in sT-induced cell migration.…”

“…MCV sT oncogenic functions induce microtubule destabilization (16) and actin rearrangement (17), which in turn, stimulates cell motility. MCV sT has also been shown to stimulate cell motility by upregulating a disintegrin and metalloproteinase domain-containing protein 10 (ADAM 10) (18).…”

Merkel cell polyomavirus small tumour antigen activates the p38 MAPK pathway to enhance cellular motility

“…The MCPyV ST interaction with PP4C also leads to microtubule destabilisation, remodelling of the actin cytoskeleton and disruption of the integrity of cell-cell junctions, driving cell migration [22]. The interaction of MCPyV ST with PP4C is also required for dephosphorylation of β1 integrins to activate Rho-GTPases, specifically cdc42 and RhoA, known to enhance cell motility and migration [23].…”

A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

“…In ∼80% of Merkel cell carcinoma (MCC) cases, Merkel cell PyV (MCPyV) infection, clonal integration and UV-mediated mutation of the viral genome occur prior to tumour cell expansion, with truncation of the large tumour antigen (LT) rendering MCPyV replication defective (4–7). Both MCPyV small T and truncated LT proteins are required for MCC survival and proliferation (8–10).…”