Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages

• Type of Material: Article
• Authors: Mei Song, Weill Cornell Medicine; Oladapo O. Yeku, Memorial Sloan Kettering Cancer Center; Sarwish Rafiq, Emory University; Terence Purdon, Memorial Sloan Kettering Cancer Center; Xue Dong, Weill Cornell Medicine; Lijing Zhu, Nanjing University; Tuo Zhang, Weill Cornell Medicine; Huan Wang, Shanghai Jiao Tong University; Ziqi Yu, Weill Cornell Medicine; Junhua Mai, Houston Methodist Research Institute; Haifa Shen, Houston Methodist Research Institute; Briana Nixon, Memorial Sloan Kettering Cancer Center; Ming Li, Memorial Sloan Kettering Cancer Center; Renier J. Brentjens, Memorial Sloan Kettering Cancer Center; Xiaojing Ma, Weill Cornell Medicine
• Language: English
• Date: 2020-12-08
• Publisher: NATURE RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-20140-0
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 11
• Issue: 1
• Start Page: 6298
• End Page: 6298
• Grant/Funding Information: This work was supported in part by an NIH award (R03CA230573 to X.M.); by an award from the Emerson Collective Cancer Research Fund (ECCRF-COR08 to X.M.); by an NIH award (5 P01 CA190174 to R.J.B.); by an institutional award (MSKCC-GC238051 to R.J.B.); by NIH awards (R01CA222959 and R01CA193880) to H.S.
• Keywords: EDD; PATHWAY; Science & Technology - Other Topics; CISPLATIN RESISTANCE; SURVIVAL; SPHEROID FORMATION; Science & Technology; TRANSCOELOMIC METASTASIS; BONE-MARROW; PROTEIN; Multidisciplinary Sciences; GENE; UBIQUITIN LIGASE UBR5
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology

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.