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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Animals
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Ascites / genetics
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Ascites / immunology
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Ascites / pathology
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Carcinoma, Ovarian Epithelial / immunology*
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Carcinoma, Ovarian Epithelial / mortality
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Carcinoma, Ovarian Epithelial / secondary
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Carcinoma, Ovarian Epithelial / therapy
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Cell Line, Tumor / transplantation
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Disease Models, Animal
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Disease Progression
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Immune Checkpoint Inhibitors / therapeutic use
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Immunotherapy, Adoptive / methods
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Macrophages, Peritoneal / immunology*
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Knockout
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Middle Aged
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Ovarian Neoplasms / immunology*
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Ovarian Neoplasms / mortality
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Ovarian Neoplasms / pathology
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Ovarian Neoplasms / therapy
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Paracrine Communication / immunology
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Peritoneal Neoplasms / immunology*
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Peritoneal Neoplasms / mortality
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Peritoneal Neoplasms / secondary
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Primary Cell Culture
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Prognosis
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Receptors, Chimeric Antigen / immunology
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Spheroids, Cellular / immunology
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Spheroids, Cellular / metabolism
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Tumor Escape / drug effects
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Tumor Escape / immunology*
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / immunology
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Immune Checkpoint Inhibitors
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Receptors, Chimeric Antigen
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UBR5 protein, human
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UBR5 protein, mouse
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Ubiquitin-Protein Ligases