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), a rare but aggressive cutaneous neoplasm with high metastatic potential, has a poor prognosis at late stages of disease with no proven chemotherapeutic regimens.,Using an enriched culture medium, we established and characterized 11 MCC cell lines for Bcl-2 family profiling and functional studies.,Immunoblot analysis revealed collectively high protein levels of pro-survival Bcl-2 members in cell lines and a panel of MCC tumors.,Down-regulation of individual Bcl-2 proteins by RNAi promoted death in a subset of MCC cell lines, whereas simultaneous inhibition of multiple family members using the small molecule antagonist ABT-263 led to dramatic induction of cell death in 10 of 11 lines.,ABT-263 induced Bax-dependent apoptosis with rapid cleavage of caspase-3 and PARP, regardless of Bcl-2 family profile or presence of Merkel cell polyomavirus.,Furthermore, ABT-263 treatment led to rapid and sustained growth suppression of MCC xenografts from a representative cell line, accompanied by a striking increase in apoptosis.,Our results establish that concurrent inhibition of multiple pro-survival Bcl-2 proteins leads to effective induction of apoptosis, and strongly support the concept that targeting MCC addiction to these molecules may be useful therapeutically by reversing an intrinsic resistance to cell death.