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

TitleTumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages.
Publication TypeJournal Article
Year of Publication2020
AuthorsSong M, Yeku OO, Rafiq S, Purdon T, Dong X, Zhu L, Zhang T, Wang H, Yu Z, Mai J, Shen H, Nixon B, Li M, Brentjens RJ, Ma X
JournalNat Commun
Volume11
Issue1
Pagination6298
Date Published2020 Dec 08
ISSN2041-1723
KeywordsAdult, Aged, Animals, Ascites, Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Disease Models, Animal, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Humans, Immune Checkpoint Inhibitors, Immunotherapy, Adoptive, Macrophages, Peritoneal, Mice, Mice, Knockout, Middle Aged, Ovarian Neoplasms, Paracrine Communication, Peritoneal Neoplasms, Primary Cell Culture, Prognosis, Receptors, Chimeric Antigen, Spheroids, Cellular, Tumor Escape, Tumor Microenvironment, Ubiquitin-Protein Ligases
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.

DOI10.1038/s41467-020-20140-0
Alternate JournalNat Commun
PubMed ID33293516
PubMed Central IDPMC7722725
Grant ListR01 CA193880 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA222959 / CA / NCI NIH HHS / United States
R03 CA230573 / CA / NCI NIH HHS / United States
P01 CA190174 / CA / NCI NIH HHS / United States

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