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Multi-Omics Analysis of Glioblastoma Cells' Sensitivity to Oncolytic Viruses
Anastasiya V Lipatova1,2, Alesya V Soboleva1, Vladimir A Gorshkov3
1V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
Abstract:
Oncolytic viruses have gained momentum in the last decades as a promising tool for cancer treatment. Despite the progress, only a fraction of patients show a positive response to viral therapy. One of the key variable factors contributing to therapy outcomes is interferon-dependent antiviral mechanisms in tumor cells. Here, we evaluated this factor using patient-derived glioblastoma multiforme (GBM) cultures. Cell response to the type I interferons' (IFNs) stimulation was characterized at mRNA and protein levels. Omics analysis revealed that GBM cells overexpress interferon-stimulated genes (ISGs) and upregulate their proteins, similar to the normal cells. A conserved molecular pattern unambiguously differentiates between the preserved and defective responses. Comparing ISGs' portraits with titration-based measurements of cell sensitivity to a panel of viruses, the "strength" of IFN-induced resistance acquired by GBM cells was ranked. The study demonstrates that suppressing a single ISG and encoding an essential antiviral protein, does not necessarily increase sensitivity to viruses. Conversely, silencing IFIT3 and PLSCR1 genes in tumor cells can negatively affect the internalization of vesicular stomatitis and Newcastle disease viruses. We present evidence of a complex relationship between the interferon response genes and other factors affecting the sensitivity of tumor cells to viruses.
Insights
Glioblastoma cells’ interferon response impacts oncolytic virus therapy. While interferon-stimulated genes are upregulated, their suppression doesn't always improve viral sensitivity, revealing complex interactions.
Area of Science:
- Oncolytic virotherapy
- Cancer immunology
- Molecular oncology
Background:
- Oncolytic viruses show promise for cancer treatment, but patient response varies.
- Interferon-dependent antiviral mechanisms in tumor cells are key factors influencing therapy outcomes.
- Glioblastoma multiforme (GBM) presents a significant challenge in cancer therapy.
Purpose of the Study:
- To evaluate the role of interferon-dependent antiviral mechanisms in patient-derived glioblastoma multiforme (GBM) cultures.
- To characterize GBM cell response to type I interferons (IFNs) at mRNA and protein levels.
- To correlate interferon-stimulated gene (ISG) expression patterns with sensitivity to oncolytic viruses.
Main Methods:
- Analysis of mRNA and protein expression of interferon-stimulated genes (ISGs) in GBM cultures upon IFN stimulation.
- Omics analysis to identify conserved molecular patterns differentiating IFN responses.
- Titration-based measurements of GBM cell sensitivity to various oncolytic viruses.
- Gene silencing of specific ISGs (IFIT3, PLSCR1) to assess impact on viral sensitivity and entry.
Main Results:
- GBM cells overexpress ISGs and their proteins, similar to normal cells, with conserved molecular patterns differentiating response strengths.
- A ranking of IFN-induced resistance in GBM cells was established by comparing ISG profiles with viral sensitivity.
- Suppressing single ISGs did not consistently increase viral sensitivity.
- Silencing IFIT3 and PLSCR1 genes impaired the internalization of specific oncolytic viruses (vesicular stomatitis and Newcastle disease viruses).
Conclusions:
- The relationship between interferon response genes and tumor cell sensitivity to oncolytic viruses is complex.
- Targeting single ISGs may not be sufficient to enhance oncolytic virotherapy efficacy.
- Understanding these intricate interactions is crucial for optimizing viral therapy in glioblastoma.
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