Understanding the Role of Delta-catenin in Virus-Positive Merkel Cell Carcinoma

Abstract

Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen and truncated large tumor (t-LT) antigen. However, the MCC cell of origin remains unknown. Identifying the cell of origin could provide critical insights into MCC pathogenesis and lead to more effective therapeutic strategies for this deadly cancer.To date, only human skin fibroblasts (HFFs) have been shown to support the complete MCPyV life cycle. Given that fibroblasts are permissive for viral replication but unlikely to be the cell of origin for MCC, we hypothesized that MCPyV initially replicates in fibroblasts but, in rare cases, infects Merkel cell progenitors or their descendants, Merkel cells, contributing to MCC development. In Chapter 2, we identified delta-catenin as a novel ST interactor in HFFs. While ST bound delta-catenin in HFFs, this interaction was absent in virus-positive (VP)-MCC cell lines. We found that while HFFs predominantly express isoform 1, a mesenchymal marker, MCC cells primarily express isoform 3, an epithelial marker. However, overexpression of delta-catenin isoform 1 in VP-MCC cells failed to restore ST binding. These results suggest that the MCC cell of origin may possess epithelial characteristics and that the host cell environment shapes delta-catenin’s function. In Chapter 3, we found that delta-catenin is essential for VP-MCC cell proliferation but was not essential for HFFs proliferation. Delta-catenin promotes proliferation in VP-MCC cells by regulating the expression of cell cycle genes through its interaction with Kaiso, a transcriptional repressor. Additionally, we found that lysine-specific histone demethylase 1A (LSD1/KDM1A) regulates delta-catenin isoform 3 expression by modulating Epithelial Splicing Regulatory Protein (ESRP1), a delta-catenin splicing factor and epithelial marker. Taken together, this work reveals novel host factors involved in MCPyV infection and MCC tumorigenesis, supporting the idea that the cells permissive for viral replication and those giving rise to MCC are distinct.