Merkel cell polyomavirus small T antigen’s role in cell motility

Merkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high likelihood of recurrence and metastasis. In 2008, Merkel cell polyomavirus (MCPyV) was discovered monoclonally integrated within the host genome of at least 80% of MCC tumours. MCPyV transforms and maintains MCC tumours via the expression of the large and small tumour (LT and ST) antigens. Specifically, ST is thought to be the major transforming factor in the tumourigenesis of MCC. Since the discovery of MCPyV, a number of mechanisms have been suggested to account for replication and tu- mour formation, but to date, little is known about potential links between MCPyV T antigen expression and the highly metastatic nature of MCC.
In this thesis, the link between MCPyV and MCC metastasis is explored by focusing on the role of MCPyV ST in promoting cell motility. Cell motility and migration is a complex, multi-step, and multi-component process, intrinsic in cancer progression and metastasis. Previous work in the Whitehouse laboratory has implicated the microtubule network in MCPyV ST-induced cell motility. This thesis builds upon those findings to show that MCPyV ST-induced cell motility is dependent on multiple factors, including the activity of integrin receptors, Rho-family GTPases and the actin cytoskeleton, and intracellular chloride channels. This thesis also further explores the MCPyV ST-PP4C interaction in MCPyV ST-induced cell motility and proposes a mechanism by which this interaction activates integrin receptors to promote cell motility, thereby contributing to the metastatic nature of MCC. Furthermore, the relocalisation of intracellular chloride channels CLIC1 and CLIC4 to the cell surface is shown to be important in MCPyV ST-induced cell motility.
Overall, results presented herein describe a novel mechanism by which
a tumour virus induces cell motility, ultimately leading to cancer metastasis. Therefore, there may be implications for the potential future therapeutic targets for disseminated MCC.