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

Mei Song, Oladapo O. Yeku, Sarwish Rafiq, Terence Purdon, Xue Dong, Lijing Zhu, Tuo Zhang, Huan Wang, Ziqi Yu, Junhua Mai, Haifa Shen, Briana Nixon, Ming Li, Renier J. Brentjens and Xiaojing Ma ()
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Mei Song: Weill Cornell Medicine
Oladapo O. Yeku: Memorial Sloan Kettering Cancer Center
Sarwish Rafiq: Memorial Sloan Kettering Cancer Center
Terence Purdon: Memorial Sloan Kettering Cancer Center
Xue Dong: Weill Cornell Medicine
Lijing Zhu: Medical School of 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

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-20140-0

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