The STING Paradox in Serous Ovarian Cancers
Abstract
Low grade serous ovarian cancer (LGSC), a rare subtype of ovarian cancer is characterized by a slow growth rate, resistance to treatment regimens, multiple recurrences and poor survival. The stimulator of interferon genes (STING), is a receptor which initiates a signaling cascade that results in an inflammatory response to cytoplasmic DNA. LGSC express high levels of STING compared to other ovarian cancers, but low levels of downstream proteins, suggesting an inactive STING pathway. We set out to characterize the defective STING signaling and whether the lack of an active STING pathway renders these tumors particularly sensitive to oncolytic viral therapy. Using proteomic profiling, we found STIM1 is more highly expressed in LGSC compared to other types of ovarian cancer. High STIM1 can anchor STING in the endoplasmic reticulum, thus preventing signaling. We have tested several oncolytic viruses and determined that the SKV vaccinia virus has superior killing compared to other vaccinia strains. Additionally, we mined our proteomic data to understand the biological differences between LGSC and its precursor lesion, serous borderline tumor (SBT). Fibroblast activation protein (FAP), a protein expressed in cancer associated fibroblasts, is abundantly expressed in LGSC. Tregs and M2 macrophages are more abundant in the stroma of LGSC compared to SBT. Together these data suggest that the tumor microenvironment provides a supportive environment for LGSC tumorigenesis and progression and that targeting the tumor microenvironment of LGSC may be a viable therapeutic strategy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1222478
Entities
People
- Dawn Cochrane