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

Author

Listed:
  • Mei Song

    (Weill Cornell Medicine)

  • Oladapo O. Yeku

    (Memorial Sloan Kettering Cancer Center
    Harvard Medical School)

  • Sarwish Rafiq

    (Memorial Sloan Kettering Cancer Center
    Winship Cancer Institute of Emory University School of Medicine)

  • 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
    Shanghai Jiao Tong University)

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.

Suggested Citation

  • 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 & Xiaojin, 2020. "Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20140-0
    DOI: 10.1038/s41467-020-20140-0
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