VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection

Rozanne Arulanandam, Cory Batenchuk, Fernando A. Angarita, Kathryn Ottolino-Perry, Sophie Cousineau, Amelia Mottashed, Emma Burgess, Theresa J. Falls, Naomi De Silva, Jovian Tsang, Grant A. Howe, Marie Claude Bourgeois-Daigneault, David P. Conrad, Manijeh Daneshmand, Caroline J. Breitbach, David H. Kirn, Leda Raptis, Subash Sad, Harold Atkins, Michael S. HuhJean Simon Diallo, Brian D. Lichty, Carolina S. Ilkow, Fabrice Le Boeuf, Christina L. Addison, J. Andrea McCart, John C. Bell

Research output: Contribution to journalArticlepeer-review

Abstract

Oncolytic viruses designed to attack malignant cells can in addition infect and destroy tumor vascular endothelial cells. We show here that this expanded tropism of oncolytic vaccinia virus to the endothelial compartment is a consequence of VEGF-mediated suppression of the intrinsic antiviral response. VEGF/VEGFR2 signaling through Erk1/2 and Stat3 leads to upregulation, nuclear localization, and activation of the transcription repressor PRD1-BF1/Blimp1. PRD1-BF1 does not contribute to the mitogenic effects of VEGF, but directly represses genes involved in type I interferon (IFN)-mediated antiviral signaling. In vivo suppression of VEGF signaling diminishes PRD1-BF1/Blimp1 expression in tumor vasculature and inhibits intravenously administered oncolytic vaccinia delivery to and consequent spread within the tumor. Arulanandam et al. show that VEGFR2 signaling in remodelling vessels induces the transcription repressor PRD1-BF1/Blimp1, which represses the expression of genes involved in type I interferon-mediated antiviral signaling, thus allowing oncolytic virus to infect tumor vasculatures to further spread within tumors.

Original languageEnglish (US)
Pages (from-to)210-224
Number of pages15
JournalCancer Cell
Volume28
Issue number2
DOIs
StatePublished - Aug 10 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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