Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma

Amy Haseley, Sean Boone, Jeffrey Wojton, Lianbo Yu, Ji Young Yoo, Jianhua Yu, Kazuhiko Kurozumi, Joseph C. Glorioso, Michael A. Caligiuri, Balveen Kaur

Research output: Contribution to journalArticle

34 Citations (Scopus)

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 α6α1, 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 a6 interactions to sensitize gliomas to viral oncolysis.

Original languageEnglish
Pages (from-to)1353-1362
Number of pages10
JournalCancer Research
Volume72
Issue number6
DOIs
Publication statusPublished - Mar 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Haseley, A., Boone, S., Wojton, J., Yu, L., Yoo, J. Y., Yu, J., Kurozumi, K., Glorioso, J. C., Caligiuri, M. A., & Kaur, B. (2012). Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma. Cancer Research, 72(6), 1353-1362. https://doi.org/10.1158/0008-5472.CAN-11-2526