WNT8B and -9B promote the survival and dissemination of dormant ovarian cancer cells

Abstract

Cancer cell dormancy and the resultant resistance to conventional therapies present significant challenges for the successful treatment of high-grade serous ovarian cancer (HGSC). We used genome wide, and specialized sgRNA, libraries in CRISPR-based screens to identify critical cell survival mechanisms in dormancy and metastasis. Our findings demonstrate that low expression Wnt ligands WNT8B and WNT9B are essential for sustaining cell survival during prolonged dormant spheroid culture conditions. These Wnt ligands utilize non-canonical signaling to activate expression of stem cell genes such as ALDH1A1, CD44 and others during spheroid dormancy. The loss of WNT8B and WNT9B reduced survival of xenografted ovarian cancer cells during early dissemination of disease that extended survival. Furthermore, treatment of WNT8B/9B deficient xenografts with carboplatin demonstrated increased sensitivity that further reduced dissemination and extended survival. These findings reveal that rare Wnt ligands can possess outsized functions in cancer pathogenesis and offer new avenues for improving treatment outcomes for HGSC through their inhibition.