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Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics

By Béatrice Cambien, Kevin Lebrigand, Alberto Baeri, Nicolas Nottet, Catherine Compin, Audrey Lamit, Olivier Ferraris, Christophe N Peyrefitte, Virginie Magnone, Jérôme Henriques, Laure-Emmanuelle Zaragosi, Sophie Giorgetti-Peraldi, Frédéric Bost, Marine Gautier-Isola, Roger Rezzonico, Pascal Barbry, Robert Barthel, Bernard Mari, Georges Vassaux

Posted 29 May 2020
bioRxiv DOI: 10.1101/2020.05.29.123133 (published DOI: 10.1371/journal.ppat.1008660)

Mammary carcinoma, including triple-negative breast carcinomas (TNBC) are tumor-types for which human and canine pathologies are closely related at the molecular level. Low-passage, primary carcinoma cells from TNBC versus non-TNBC were used to compare the efficacy of an oncolytic vaccinia virus (VV).  We show that non-TNBC cells are 28 times more sensitive to VV than TNBC cells in which VV replication is impaired. Single-cell RNA-seq performed on two different TNBC cell samples infected or not with VV highlighted three distinct populations: naïve cells, bystander cells, defined as cells exposed to the virus but not infected and infected cells. The transcriptome of these three populations showed striking variations in the modulation of pathways regulated by cytokines and growth factors. We hypothesized that the pool of genes expressed in the bystander populations was enriched in antiviral genes. Bio-informatic analysis suggested that the reduced activity of the virus was associated with a higher mesenchymal status of the cells. In addition, we demonstrate experimentally that high expression of one gene, DDIT4, is detrimental to VV production. Considering that DDIT4 is associated with a poor prognosis in various cancers including TNBC, out data highlight DDIT4 as a candidate resistance marker for oncolytic poxvirus therapy. This information could be used to design new generations of oncolytic poxviruses. Beyond the field of gene therapy, this study demonstrate that single-cell transcriptomics can be used to identify cellular factors influencing viral replication

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