TY - JOUR
T1 - Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages
AU - Song, Mei
AU - Yeku, Oladapo O.
AU - Rafiq, Sarwish
AU - Purdon, Terence
AU - Dong, Xue
AU - Zhu, Lijing
AU - Zhang, Tuo
AU - Wang, Huan
AU - Yu, Ziqi
AU - Mai, Junhua
AU - Shen, Haifa
AU - Nixon, Briana
AU - Li, Ming
AU - Brentjens, Renier J.
AU - Ma, Xiaojing
N1 - Funding Information:
This work was supported in part by an NIH award (R03CA230573 to X.M.); by an award from the Emerson Collective Cancer Research Fund (ECCRF-COR08 to X.M.); by an NIH award (5 P01 CA190174 to R.J.B.); by an institutional award (MSKCC-GC238051 to R.J.B.); by NIH awards (R01CA222959 and R01CA193880) to H.S.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/8
Y1 - 2020/12/8
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Animals
KW - Ascites/genetics
KW - Carcinoma, Ovarian Epithelial/immunology
KW - Cell Line, Tumor/transplantation
KW - Disease Models, Animal
KW - Disease Progression
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Immune Checkpoint Inhibitors/therapeutic use
KW - Immunotherapy, Adoptive/methods
KW - Macrophages, Peritoneal/immunology
KW - Mice
KW - Mice, Knockout
KW - Middle Aged
KW - Ovarian Neoplasms/immunology
KW - Paracrine Communication/immunology
KW - Peritoneal Neoplasms/immunology
KW - Primary Cell Culture
KW - Prognosis
KW - Receptors, Chimeric Antigen/immunology
KW - Spheroids, Cellular/immunology
KW - Tumor Escape/drug effects
KW - Tumor Microenvironment/drug effects
KW - Ubiquitin-Protein Ligases/genetics
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UR - http://www.scopus.com/inward/citedby.url?scp=85097444542&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-20140-0
DO - 10.1038/s41467-020-20140-0
M3 - Article
C2 - 33293516
AN - SCOPUS:85097444542
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6298
ER -