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. Huh; Jean Simon Diallo; Brian D. Lichty; Carolina S. Ilkow; Fabrice Le Boeuf; Christina L. Addison; J. Andrea McCart; John C. Bell

doi:10.1016/j.ccell.2015.06.009

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 journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	210-224
Number of pages	15
Journal	Cancer Cell
Volume	28
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2015.06.009
State	Published - Aug 10 2015

ASJC Scopus subject areas

Oncology
Cancer Research

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Arulanandam, R., Batenchuk, C., Angarita, F. A., Ottolino-Perry, K., Cousineau, S., Mottashed, A., Burgess, E., Falls, T. J., De Silva, N., Tsang, J., Howe, G. A., Bourgeois-Daigneault, M. C., Conrad, D. P., Daneshmand, M., Breitbach, C. J., Kirn, D. H., Raptis, L., Sad, S., Atkins, H., ... Bell, J. C. (2015). VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection. Cancer Cell, 28(2), 210-224. https://doi.org/10.1016/j.ccell.2015.06.009

Arulanandam, R, Batenchuk, C, Angarita, FA, Ottolino-Perry, K, Cousineau, S, Mottashed, A, Burgess, E, Falls, TJ, De Silva, N, Tsang, J, Howe, GA, Bourgeois-Daigneault, MC, Conrad, DP, Daneshmand, M, Breitbach, CJ, Kirn, DH, Raptis, L, Sad, S, Atkins, H, Huh, MS, Diallo, JS, Lichty, BD, Ilkow, CS, Le Boeuf, F, Addison, CL, McCart, JA & Bell, JC 2015, 'VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection', Cancer Cell, vol. 28, no. 2, pp. 210-224. https://doi.org/10.1016/j.ccell.2015.06.009

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = aug,

day = "10",

doi = "10.1016/j.ccell.2015.06.009",

language = "English (US)",

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AU - Arulanandam, Rozanne

AU - Batenchuk, Cory

AU - Angarita, Fernando A.

AU - Ottolino-Perry, Kathryn

AU - Cousineau, Sophie

AU - Mottashed, Amelia

AU - Burgess, Emma

AU - Falls, Theresa J.

AU - De Silva, Naomi

AU - Tsang, Jovian

AU - Howe, Grant A.

AU - Bourgeois-Daigneault, Marie Claude

AU - Conrad, David P.

AU - Daneshmand, Manijeh

AU - Breitbach, Caroline J.

AU - Kirn, David H.

AU - Raptis, Leda

AU - Sad, Subash

AU - Atkins, Harold

AU - Huh, Michael S.

AU - Diallo, Jean Simon

AU - Lichty, Brian D.

AU - Ilkow, Carolina S.

AU - Le Boeuf, Fabrice

AU - Addison, Christina L.

AU - McCart, J. Andrea

AU - Bell, John C.

PY - 2015/8/10

Y1 - 2015/8/10

N2 - 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.

AB - 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.

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JF - Cancer Cell

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ER -

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

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