title: Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: role of type I interferon signaling.
abstract: Oncolytic virus (OV) therapy takes advantage of common cancer characteristics, such as defective type I interferon (IFN) signaling, to preferentially infect and kill cancer cells with viruses. Our recent study (Murphy et al., 2012. J. Virol. 86, 3073-87) found human pancreatic ductal adenocarcinoma (PDA) cells were highly heterogeneous in their permissiveness to vesicular stomatitis virus (VSV) and suggested at least some resistant cell lines retained functional type I IFN responses. Here we examine cellular responses to infection by the oncolytic VSV recombinant VSV-ΔM51-GFP by analyzing a panel of 11 human PDA cell lines for expression of 33 genes associated with type I IFN pathways. Although all cell lines sensed infection by VSV-ΔM51-GFP and most activated IFN-α and β expression, only resistant cell lines displayed constitutive high-level expression of the IFN-stimulated antiviral genes MxA and OAS. Inhibition of JAK/STAT signaling decreased levels of MxA and OAS and increased VSV infection, replication and oncolysis, further implicating IFN responses in resistance. Unlike VSV, vaccinia and herpes simplex virus infectivity and killing of PDA cells was independent of the type I IFN signaling profile, possibly because these two viruses are better equipped to evade type I IFN responses. Our study demonstrates heterogeneity in the type I IFN signaling status of PDA cells and suggests MxA and OAS as potential biomarkers for PDA resistance to VSV and other OVs sensitive to type I IFN responses.
authors.affiliation: Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Moerdyk-Schauwecker
authors.forename: Nirav R
authors.initials: NR
authors.lastname: Shah
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Murphy
authors.forename: Eric
authors.initials: E
authors.lastname: Hastie
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
authors.forename: Valery Z
authors.initials: VZ
authors.lastname: Grdzelishvili
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D064547:Myxovirus Resistance Proteins; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000628:therapy* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018353:Rhabdoviridae Infections; D015398:Signal Transduction; D054243:Vesicular Stomatitis; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
chemical_list: D014408:Biomarkers, Tumor; D007370:Interferon Type I; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D053612:Janus Kinases; D015088:2',5'-Oligoadenylate Synthetase; D019204:GTP-Binding Proteins