TWEAK-Fn14-RelB Signaling Cascade Promotes Stem Cell-like Features that Contribute to Post-Chemotherapy Ovarian Cancer Relapse

Disease recurrence in high-grade serous ovarian cancer may be due to cancer stem-like cells (CSC) that are resistant to chemo-therapy and capable of reestablishing heterogeneous tumors. The alternative NF-xB signaling pathway is implicated in this process; however, the mechanism is unknown. Here we show that TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are strong inducers of alternative NF-xB signaling and are enriched in ovarian tumors following chemotherapy treatment. We further show that TWEAK enhances spheroid formation ability, asymmet-ric division capacity, and expression of SOX2 and epithelial-to-mesenchymal transition genes VIM and ZEB1 in ovarian cancer cells, phenotypes that are enhanced when TWEAK is combined with carboplatin. Moreover, TWEAK in combination with chemo-therapy induces expression of the CSC marker CD117 in CD117- cells. Blocking the TWEAK-Fn14-RelB signaling cascade with a small-molecule inhibitor of Fn14 prolongs survival following car-boplatin chemotherapy in a mouse model of ovarian cancer. These data provide new insights into ovarian cancer CSC biology and highlight a signaling axis that should be explored for therapeutic development. Implications: This study identifies a unique mechanism for the induction of ovarian cancer stem cells that may serve as a novel therapeutic target for preventing relapse.

Automated summary

Disease recurrence in high-grade serous ovarian cancer may be attributed to resistant cancer stem-like cells (CSC) that can reestablish tumors. The study reveals that the TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, play a role in activating the alternative NF-xB signaling pathway in ovarian tumors after chemotherapy. Furthermore, TWEAK enhances the characteristics of CSCs and induces the expression of the CSC marker CD117 in ovarian cancer cells. Blocking the TWEAK-Fn14-RelB signaling cascade prolongs survival in a mouse model of ovarian cancer treated with carboplatin chemotherapy.