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Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction
Paige E Solomon1, Lisa L Kirkemo1, Gary M Wilson2
1Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
Abstract:
Since the discovery of oncogenes, there has been tremendous interest to understand their mechanistic basis and to develop broadly actionable therapeutics. Some of the most frequently activated oncogenes driving diverse cancers are c-MYC, EGFR, HER2, AKT, KRAS, BRAF, and MEK. Using a reductionist approach, we explored how cellular proteomes are remodeled in isogenic cell lines engineered with or without these driver oncogenes. The most striking discovery for all oncogenic models was the systematic downregulation of scores of antiviral proteins regulated by type 1 interferon. These findings extended to cancer cell lines and patient-derived xenograft models of highly refractory pancreatic cancer and osteosarcoma driven by KRAS and MYC oncogenes. The oncogenes reduced basal expression of and autocrine stimulation by type 1 interferon causing remarkable convergence on common phenotypic and functional profiles. In particular, there was dramatically lower expression of dsRNA sensors including DDX58 (RIG-I) and OAS proteins, which resulted in attenuated functional responses when the oncogenic cells were treated with the dsRNA mimetic, polyI:C, and increased susceptibility to infection with an RNA virus shown using SARS-CoV-2. Our reductionist approach provides molecular and functional insights connected to immune evasion hallmarks in cancers and suggests therapeutic opportunities.
Insights
Common cancer-driving oncogenes suppress antiviral defenses by downregulating type 1 interferon-stimulated genes. This impairs cancer cells' response to viral mimics and increases susceptibility to RNA viruses, offering new therapeutic avenues.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Oncogenes like c-MYC, KRAS, and BRAF are frequently activated in various cancers.
- Understanding their mechanistic basis is crucial for developing targeted therapeutics.
- Driver oncogenes remodel cellular proteomes, impacting cancer progression and immune response.
Purpose of the Study:
- To investigate how driver oncogenes remodel cellular proteomes.
- To identify common molecular and functional profiles associated with oncogene activation.
- To explore the link between oncogene-driven proteome remodeling and immune evasion.
Main Methods:
- Utilized isogenic cell lines engineered with specific driver oncogenes.
- Analyzed proteome remodeling in response to oncogene activation.
- Examined expression of antiviral proteins, including dsRNA sensors (DDX58, OAS).
- Assessed functional responses to dsRNA mimics (polyI:C) and RNA virus infection (SARS-CoV-2).
Main Results:
- Systematic downregulation of type 1 interferon-regulated antiviral proteins was observed across all oncogenic models.
- This downregulation occurred in engineered cell lines, cancer cell lines, and patient-derived xenografts.
- Reduced expression of dsRNA sensors led to attenuated responses to polyI:C and increased susceptibility to SARS-CoV-2 infection.
- Oncogenes decreased basal type 1 interferon expression and autocrine stimulation.
Conclusions:
- Driver oncogenes converge on a common mechanism of suppressing antiviral immunity.
- This suppression involves downregulation of type 1 interferon signaling and dsRNA sensors.
- These findings provide insights into cancer immune evasion and suggest potential therapeutic strategies targeting antiviral pathways.
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