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

Song, Mei; Yeku, Oladapo; Rafiq, Sarwish; Purdon, Terence J.; Dong, Xue; Zhu, Lijing; Zhang, Tuo; Wang, Huan; Yu, Ziqi; Mai, Junhua; Shen, Haifa; Nixon, Briana G.; Li, Ming; Brentjens, Renier J.; Ma, Xiaojing

doi:10.1038/s41467-020-20140-0

Cited by 94 publications

(68 citation statements)

References 49 publications

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“…To systematically identify essential genes that regulate the transcoelomic metastasis of OC, we used GeCKO (v2) sgRNA pooled libraries to perform genome-wide gene knockout in SK-OV-3 cells 18 . SK-OV-3 cells are well differentiated serous adenocarcinoma cells and can form xenograft tumors with a histology that is also very similar to a human serous ovarian cancer 19 , 20 . We screened cancer cells with highly peritoneal metastatic capacity in an orthotopic murine OC model and performed a high throughput DNA sequencing analysis (Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

Serotonin/HTR1E signaling blocks chronic stress-promoted progression of ovarian cancer

Qin

Wang

et al. 2021

Theranostics

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Rationale: Psychological stress has been linked to cancer development and resistance to therapy by many epidemiological and clinical studies. Stress-induced immunosuppressive microenvironment by stress hormones, in particular glucocorticoids, has been extensively studied. However, the impacts of other stress-related neurotransmitters, such as serotonin (5-hydroxytryptamine, 5-HT), on cancer development just start to be revealed. Here, we aimed to identify novel neurotransmitters involved in stress-induced growth and dissemination of ovarian cancer (OC) and reveal the major underlying signaling pathway and the therapeutic significance. Methods: Through a genome-wide CRISPR/Cas9 knockout screen in the murine orthotopic model of ovarian carcinoma (OC), we identified candidate genes regulating the peritoneal dissemination of OC. Among them, we picked out HTR1E, one member of 5-HT receptor family specifically expressed in the ovary and endometrium in addition to brain. The correlation of HTR1E expression with OC progression was analyzed in OC patient specimen by quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry (IHC). Gain-of-function and loss-of-function analyses were performed to explore the functions of 5-HT/HTR1E signaling in OC growth and dissemination in vitro and in vivo . In addition, we investigated the therapeutic values of HTR1E specific agonist and small molecular inhibitors against HTR1E downstream factor SRC in a stressed murine OC xenograft model. Results: In OC patients, the HTR1E expression is dramatically decreased in peritoneal disseminated OC cells, which correlates with poor clinical outcome. Silence of HTR1E in OC cells greatly promotes cell proliferation and epithelial mesenchymal transition (EMT) by the activation of SRC-mediated downstream signaling pathways. Furthermore, chronic stress results in significantly decreased serotonin in the ovary and the enhanced OC growth and peritoneal dissemination in mice, which can be strongly inhibited by specific HTR1E agonist or the SRC inhibitor. Conclusions: We discovered the essential role of serotonin/HTR1E signaling in preventing the chronic psychological stress-promoted progression of OC, suggesting the potential therapeutic value of the HTR1E specific agonist and the SRC inhibitor for OC patients who are suffering from psychological stress.

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Section: Resultsmentioning

confidence: 99%

Serotonin/HTR1E signaling blocks chronic stress-promoted progression of ovarian cancer

Qin

Wang

et al. 2021

Theranostics

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“…The role of macrophages in maintaining the immunosuppressive microenvironment and promoting cancer progression has been well studied, 25 , 26 and CSF-1/CSF-1R signaling is important for macrophage recruitment and polarization. 27 , 28 We also detected constitutive secretion of CSF-1 by ID8 cells (data not shown) and high expression of CSF-1R on macrophages ( Figure 2 J).…”

Section: Resultsmentioning

confidence: 99%

Oncolytic adenovirus inhibits malignant ascites of advanced ovarian cancer by reprogramming the ascitic immune microenvironment

Shi

et al. 2021

Molecular Therapy - Oncolytics

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Malignant ascites frequently occur in patients with advanced ovarian cancer at initial diagnosis, and in almost all cases of relapse, they are closely related to poor prognosis, chemoresistance, and metastasis. To date, effective management strategies have been limited. In this study, we aimed to investigate the effects of oncolytic adenovirus (OV) on malignant ascites in a mouse model of advanced ovarian cancer. The results suggested that OV conferred an effective ability to reduce ascites development and prolong overall survival. Further analysis of the ascitic immune microenvironment revealed that OV treatment promoted T cell infiltration, activation, and differentiation into the effector phenotype; reprogrammed macrophages toward the M1-like phenotype; and increased the ratios of both CD8 + T cells to CD4 + T cells and M1 to M2 macrophages. However, immunosuppressive factors such as PD-1, LAG-3, and Tregs emerged after treatment. Combination therapy including OV, CSF-1R inhibitor PLX3397, and anti-PD-1 remarkably delayed the progression of ascites, and combination therapy induced a greater extent of T cell infiltration, proliferation, and activation. This study provides experimental and theoretical evidence for oncolytic virus-based treatment of malignant ascites, which may further contribute to advanced ovarian cancer therapy.

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“…These results suggested that the interaction between OBFC2A and tumor-associated macrophages may drive the development of breast cancer. Tumor-derived UBR5 was essential for cancer progression by promoting tumor-associated macrophage recruitment and activation via key chemokines and cytokines ( 27 ). It also showed that targeting tumor-associated macrophage-related gene (OBFC2A) may have broader implications for improving the effectiveness of cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

The Potential Prognostic Role of Oligosaccharide-Binding Fold-Containing Protein 2A (OBFC2A) in Triple-Negative Breast Cancer

Tang

Zhu

et al. 2021

Front. Oncol.

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BackgroundPatients with triple-negative breast cancer (TNBC) have poor overall survival. The present study aimed to investigate the potential prognostics of TNBC by analyzing breast cancer proteomic and transcriptomic datasets.MethodsCandidate proteins selected from CPTAC (the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium) were validated using datasets from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium). Kaplan-Meier analysis and ROC (receiver operating characteristic) curve analysis were performed to explore the prognosis of candidate genes. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis were performed on the suspected candidate genes. Single-cell RNA-seq (scRNA-seq) data from GSE118389 were used to analyze the cell clusters in which OBFC2A (Oligosaccharide-Binding Fold-Containing Protein 2A) was mainly distributed. TIMER (Tumor Immune Estimation Resource) was used to verify the correlation between OBFC2A expression and immune infiltration. Clone formation assays and wound healing assays were used to detect the role of OBFC2A expression on the proliferation, invasion, and migration of breast cancer cells. Flow cytometry was used to analyze the effects of silencing OBFC2A on breast cancer cell cycle and apoptosis.ResultsSix candidate proteins were found to be differentially expressed in non-TNBC and TNBC groups from CPTAC. However, only OBFC2A was identified as an independently poor prognostic gene marker in METABRIC (HR=3.658, 1.881-7.114). And OBFC2A was associated with immune functions in breast cancer. Biological functional experiments showed that OBFC2A might promote the proliferation and migration of breast cancer cells. The inhibition of OBFC2A expression blocked the cell cycle in G1 phase and inhibited the transformation from G1 phase to S phase. Finally, downregulation of OBFC2A also increased the total apoptosis rate of cells.ConclusionOn this basis, OBFC2A may be a potential prognostic biomarker for TNBC.

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

Cited by 94 publications

References 49 publications

Serotonin/HTR1E signaling blocks chronic stress-promoted progression of ovarian cancer

Serotonin/HTR1E signaling blocks chronic stress-promoted progression of ovarian cancer

Oncolytic adenovirus inhibits malignant ascites of advanced ovarian cancer by reprogramming the ascitic immune microenvironment

The Potential Prognostic Role of Oligosaccharide-Binding Fold-Containing Protein 2A (OBFC2A) in Triple-Negative Breast Cancer

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