title: Epithelial-mesenchymal transition enhances response to oncolytic herpesviral therapy through nectin-1.
abstract: Cancers exhibiting epithelial-mesenchymal transition (EMT) are associated with aggressive behavior and increased metastatic potential. Therapies that are able to target EMT would have significant clinical value. Nectin-1 is a cell surface herpes simplex virus type 1 (HSV-1) receptor that also forms a component of intercellular adherens junctions, which are typically disrupted in EMT. To explore relationships between HSV-1 sensitivity and EMT, we generated cell lines with a stable EMT phenotype from human follicular thyroid cancer (WRO82-1) through E-cadherin silencing with short hairpin RNA (shEcadWRO). HSV-1 viral attachment and gene expression were both enhanced in shEcadWRO as compared with shControl. Immunoblotting and immunostaining revealed enhanced nectin-1 expression by shEcadWRO. Receptor-blocking assays demonstrated that increased herpesviral entry into shEcadWRO as compared with shControl was mediated predominantly through nectin-1. Colocalization of green fluorescent protein-tagged HSV-1 and tdTomato-tagged nectin-1 confirmed an increase in viral attachment to nectin-1 in shEcadWRO. Cell viability assays demonstrated increased susceptibility of shEcadWRO to HSV-1 oncolysis, and a murine flank tumor model showed significantly enhanced regression of shEcadWRO tumors in response to oncolytic HSV-1 as compared with control tumors. A separate model of EMT induction through transforming growth factor-β stimulation confirmed enhanced HSV-1 susceptibility in Panc1 cells. These results demonstrate that the process of EMT leads to increased herpesviral susceptibility through enhanced cell surface nectin-1 expression, suggesting that cancers exhibiting EMT may be naturally sensitive targets for herpesviral therapy.
authors.affiliation: 1 Department of Surgery, Memorial Sloan-Kettering Cancer Center , New York, NY 10021.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Chen
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Chen
authors.forename: Shu-Fu
authors.initials: SF
authors.lastname: Lin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wong
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D000075983:Nectins; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D047368:Tumor Burden; D053585:Virus Attachment; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins