title: Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma.
abstract: Oncolytic viral therapy has been explored widely as an option for glioma treatment but its effectiveness has remained limited. Cysteine rich 61 (CCN1) is an extracellular matrix (ECM) protein elevated in cancer cells that modulates their adhesion and migration by binding cell surface receptors. In this study, we examined a hypothesized role for CCN1 in limiting the efficacy of oncolytic viral therapy for glioma, based on evidence of CCN1 induction that occurs in this setting. Strikingly, we found that exogenous CCN1 in glioma ECM orchestrated a cellular antiviral response that reduced viral replication and limited cytolytic efficacy. Gene expression profiling and real-time PCR analysis revealed a significant induction of type-I interferon responsive genes in response to CCN1 exposure. This induction was accompanied by activation of the Jak/Stat signaling pathway, consistent with induction of an innate antiviral cellular response. Both effects were mediated by the binding of CCN1 to the cell surface integrin α6β1, activating its signaling and leading to rapid secretion of interferon-α, which was essential for the innate antiviral effect. Together, our findings reveal how an integrin signaling pathway mediates activation of a type-I antiviral interferon response that can limit the efficacy of oncolytic viral therapy. Furthermore, they suggest therapeutic interventions to inhibit CCN1-integrin α6 interactions to sensitize gliomas to viral oncolysis.
authors.affiliation: Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Haseley
authors.forename: Sean
authors.initials: S
authors.lastname: Boone
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wojton
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kurozumi
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Glorioso
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D055515:Cysteine-Rich Protein 61 / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D005910:Glioma / Q000628:therapy*; D006801:Humans; D039121:Integrin alpha6beta1 / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D015398:Signal Transduction
chemical_list: C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D039121:Integrin alpha6beta1; D007370:Interferon Type I; D016898:Interferon-alpha