TY - JOUR
T1 - VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection
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.
N1 - Funding Information:
J.C.B. is supported by a Terry Fox Foundation (TFF) Grant, the Canadian Cancer Society Research Institute (CCSRI), the Ontario Institute for Cancer Research (OICR), the Canadian Institute for Health Research (CIHR), the Ottawa Regional Cancer Foundation, and the Ottawa Hospital Foundation. R.A. was supported by a Mitacs Elevate Industrial Fellowship. C.B. was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) scholarship. S.C. was supported by an NSERC award. L.R. is funded by NSERC, CIHR, and the Canadian Breast Cancer Foundation (CBCF). S.S. is supported by CIHR. C.S.I. was supported by a fellowship from the Alberta Innovates Health Solutions. J.-S.D. is supported by TFF, CIHR, and CCSRI. B.D.L. is supported by CIHR and OICR. J.A.M. is funded by OICR, CCSRI, and CIHR. We thank the J.C.B., J.-S.D., H.A., and Rebecca Auer labs for constructive critique and support. Thanks to M.A. Christine Pratt and Miguel A. Cabrita for guidance, Ellias Horner and Alexandre Blais for imaging, Christiano Souza for assistance with animal injections, Ana Giassi and Zaida Ticas for prompt histology services, and Pamela S. Lagali for confocal imaging. C.J.B. is an employee of Sillajen Biotherapeutics. J.C.B., D.H.K., and H.A. were co-founders of Jennerex Biotherapeutics. J.C.B. and B.D.L. are co-founders of Turnstone Biologics.
Publisher Copyright:
© 2015 Elsevier Inc.
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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UR - http://www.scopus.com/inward/citedby.url?scp=84939471765&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2015.06.009
DO - 10.1016/j.ccell.2015.06.009
M3 - Article
C2 - 26212250
AN - SCOPUS:84939471765
VL - 28
SP - 210
EP - 224
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 2
ER -