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

  • 0Université Côte d'Azur, CEA, Laboratoire TIRO, Nice France.
Plos Pathogens +

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October 19, 2020

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October 19, 2020

View abstract on PubMed

Summary

This summary is machine-generated.

Triple-negative breast carcinoma (TNBC) is less sensitive to oncolytic vaccinia virus (VV) due to impaired replication. DDIT4 gene expression hinders VV production, identifying it as a potential resistance marker for oncolytic poxvirus therapy.

Area Of Science

  • Oncology
  • Virology
  • Genomics

Background

  • Human and canine mammary carcinomas, including triple-negative breast carcinomas (TNBC), share molecular similarities.
  • Oncolytic viruses are a promising cancer therapy, but their efficacy can vary significantly between tumor types.

Purpose Of The Study

  • To compare the efficacy of oncolytic vaccinia virus (VV) in TNBC versus non-TNBC cells.
  • To investigate the cellular mechanisms underlying VV resistance in TNBC.
  • To identify potential biomarkers for predicting response to oncolytic poxvirus therapy.

Main Methods

  • Comparison of VV sensitivity in primary TNBC and non-TNBC cells.
  • Single-cell RNA sequencing (scRNA-seq) of VV-infected and uninfected TNBC cells to identify distinct cell populations (naïve, bystander, infected).
  • Bioinformatic analysis of transcriptomic data to identify modulated pathways and cellular factors affecting VV replication.
  • Experimental validation of the role of DDIT4 in VV production.

Main Results

  • Non-TNBC cells were significantly more sensitive to VV than TNBC cells, with impaired VV replication in TNBC.
  • scRNA-seq revealed distinct naïve, bystander, and infected cell populations with significant transcriptomic variations, particularly in cytokine and growth factor pathways.
  • Reduced VV activity in TNBC was associated with a higher mesenchymal cell status.
  • High expression of the DDIT4 gene was experimentally confirmed to be detrimental to VV production.

Conclusions

  • DDIT4 is a key factor limiting VV replication in TNBC and represents a potential resistance marker for oncolytic poxvirus therapy.
  • Understanding cellular factors influencing viral replication, like DDIT4, can guide the development of next-generation oncolytic viruses.
  • Single-cell transcriptomics is a powerful tool for identifying cellular determinants of viral replication in gene therapy contexts.