Abstract :
[en] Mammary carcinoma, including triple-negative breast carcinomas (TNBC) are tumor-types
for which human and canine pathologies are closely related at the molecular level. The efficacy of an oncolytic vaccinia virus (VV) was compared in low-passage primary carcinoma
cells from TNBC versus non-TNBC. Non-TNBC cells were 28 fold 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 transcriptomes 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. Bioinformatic analysis suggested that the reduced activity of the virus was associated with a
higher mesenchymal status of the cells. In addition, we demonstrated 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, our 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 demonstrates that single-cell transcriptomics can be used to identify cellular factors influencing viral replication.
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