Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages.
Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages.
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肿瘤来源的泛素蛋白连接酶5（UBR5）通过诱导免疫抑制性巨噬细胞促进卵巢癌的生长和转移。
DOI：
10.1038/s41467-020-20140-0
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发表时间：
2020-12-08
影响因子：
16.6
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Song 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
免疫抑制性肿瘤微环境（TME）和腹水源性球体在卵巢癌（OC）中促进肿瘤生长和进展，也是癌症治疗的主要障碍。参与OC-TME相互作用的分子途径，串扰如何影响OC攻击和耐药性尚未得到很好的表征。在这里，我们证明了肿瘤衍生的UBR 5，一种在人OC中过表达的与预后不良相关的E3连接酶，主要通过促进肿瘤相关的巨噬细胞的募集和激活，通过关键的趋化因子和细胞因子，对OC进展至关重要。UBR 5还需要维持细胞内在β-连环蛋白介导的信号传导，以通过控制p53蛋白水平来促进细胞粘附/定殖和类器官形成。OC特异性靶向UBR 5强烈增强了常规化疗和免疫疗法的生存益处。这项工作提供了对UBR 5在调节OC-TME串扰中的新型癌基因样功能的机制见解，并表明UBR 5是OC治疗中用于调节TME和癌症干性的潜在治疗靶点。卵巢癌细胞经常转移到腹膜腔，形成球状结构并促进高度免疫抑制的肿瘤微环境。在这里，作者表明，泛素连接酶UBR 5是卵巢癌生长和转移所必需的，维持球体形成和免疫抑制性肿瘤相关巨噬细胞的浸润。
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. Ovarian cancer cells often metastasize to the peritoneal cavity, forming spheroid-like structures and promoting a highly immunosuppressive tumor microenvironment. Here, the authors show that the ubiquitin ligase UBR5 is required for ovarian cancer growth and metastasis, sustaining spheroid formation and the infiltration of immunosuppressive tumor associated macrophages.
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DOI：
10.1073/pnas.1100132108
发表时间：
2011-10-25
影响因子：
11.1
作者：
Dompe, Nicholas;Rivers, Celina Sanchez;Davis, David P.
通讯作者：
Davis, David P.
影响因子：
50.3
作者：
Huang Y;Snuderl M;Jain RK
通讯作者：
Jain RK
影响因子：
4.8
作者：
Ling, Shiyun;Lin, Weei-Chin
通讯作者：
Lin, Weei-Chin
影响因子：
64.5
作者：
Cubillos-Ruiz JR;Silberman PC;Rutkowski MR;Chopra S;Perales-Puchalt A;Song M;Zhang S;Bettigole SE;Gupta D;Holcomb K;Ellenson LH;Caputo T;Lee AH;Conejo-Garcia JR;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
7.2
作者：
Koneru, Mythili;Purdon, Terence J.;Brentjens, Renier J.
通讯作者：
Brentjens, Renier J.