Abstract A071: Characterization of TWEAK in an immunocompetent murine ovarian cancer model

Abstract High-Grade Serous Ovarian Cancer (HGSOC) is the most lethal gynecologic malignancy in the US, with 90% of patients experiencing resistance to standard-of-care chemotherapies, Carboplatin and Paclitaxel. Research implicates cancer stem-like cells (CSCs), a subpopulation of quiescent, multipotent cells. Our previous findings identified TWEAK, a pro-inflammatory cytokine, as a critical mediator of CSCs including spheroid formation, chemoresistance, and stem gene expression. TWEAK seem to induce chemosensitivity or chemoresistance in cancer cells, but this mechanism is ill-defined. Furthermore, the role of the immune system in modulating TWEAK activity is understudied. We hypothesize that in an immunocompetent model, TWEAK contributes to induction of CSC characteristics in the post-chemotherapy tumor microenvironment. Previous studies indicate murine ovarian surface epithelial cell lines ID8 and p53-mutant ID8 recapitulate human tumor microenvironment. To study the combination of Carboplatin and Paclitaxel, we calculated IC50 values in ID8 cell lines and found that p53-mutant cells are significantly more chemosensitive than wild-type cells. Next, we assessed a panel of surface markers by flow cytometry, including TWEAK receptor, Fn14, and CSC markers LGR5, GRP78, CD117, and αVβ3. Baseline expression of these markers was less than 5% for LGR5 and αVβ3 in both cell lines. Following chemotherapy treatment, LGR5, Fn14, and αVβ3 increased expression in both cell lines, while GRP78 only increased in p53-mutant cells. Further research will utilize FACS to sort for CSCs using the identified markers and comparing a panel of stem genes for both ID8 cell lines. Future work will investigate ID8 cell lines in CSC functional assays including spheroid formation, chemoresistance assays, and in vivo murine relapse models. Utilizing an immunocompetent mouse model to study the interaction of TWEAK with CSCs provides promising insights into the mechanisms driving chemoresistance. Citation Format: Harshada Sapre. Characterization of TWEAK in an immunocompetent murine ovarian cancer model abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl): Abstract nr A071.