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, Xiaojing Ma

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number6298
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - Dec 8 2020

Keywords

  • Adult
  • Aged
  • Animals
  • Ascites/genetics
  • Carcinoma, Ovarian Epithelial/immunology
  • Cell Line, Tumor/transplantation
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune Checkpoint Inhibitors/therapeutic use
  • Immunotherapy, Adoptive/methods
  • Macrophages, Peritoneal/immunology
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Ovarian Neoplasms/immunology
  • Paracrine Communication/immunology
  • Peritoneal Neoplasms/immunology
  • Primary Cell Culture
  • Prognosis
  • Receptors, Chimeric Antigen/immunology
  • Spheroids, Cellular/immunology
  • Tumor Escape/drug effects
  • Tumor Microenvironment/drug effects
  • Ubiquitin-Protein Ligases/genetics

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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