Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages
Mei Song, Oladapo Yeku, Sarwish Rafiq, Terence J. Purdon, Xue Dong, Lijing Zhu, Tuo Zhang, Huan Wang, Ziqi Yu, Junhua Mai, Haifa Shen, Briana G. Nixon, Ming O. Li, Renier J. Brentjens, Xiaojing Ma
Abstract
Immunosuppressive tumor microenvironment (TME) and ascites-derived spheroids in ovarian cancer (OC) facilitate tumor growth and progression, and also pose major obstacles for cancer therapy. The molecular pathways involved in the OC-TME interactions, how the crosstalk impinges on OC aggression and chemoresistance are not well-characterized. Here, we demonstrate that tumor-derived UBR5, an E3 ligase overexpressed in human OC associated with poor prognosis, is essential for OC progression principally by promoting tumor-associated macrophage recruitment and activation via key chemokines and cytokines. UBR5 is also required to sustain cell-intrinsic β-catenin-mediated signaling to promote cellular adhesion/colonization and organoid formation by controlling the p53 protein level. OC-specific targeting of UBR5 strongly augments the survival benefit of conventional chemotherapy and immunotherapies. This work provides mechanistic insights into the novel oncogene-like functions of UBR5 in regulating the OC-TME crosstalk and suggests that UBR5 is a potential therapeutic target in OC treatment for modulating the TME and cancer stemness.