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Oncogenic RAD21 Amplification Suppresses Interferon Signalling to Promote Immune Evasion in Ovarian Cancer

ABSTRACT: Ovarian cancer (OV) is the leading cause of mortality from gynaecological malignancies with poor prognosis and limited therapeutic options. Prevalent copy number alteration (CNA) is a genetic characteristic of OV, but its contribution to tumorigenesis remain unclear. Here, we identify RAD21, a component of the cohesin complex, as a frequently amplified and overexpressed oncogene in high grade serous ovarian cancer (HGSOC), the most common subtype of OV. RAD21 copy number amplification and overexpression are correlated with poor prognosis in HGSOC. In HGSOC cells and xenograft models, depletion of RAD21 inhibited cell proliferation by inducing mitotic phase arrest and thereby reducing tumour growth, whereas overexpression of RAD21 conferred resistance to carboplatin. Mechanistically, we found that RAD21 interacts with YAP/TEAD4 transcriptional co-repressors and recruits NuRD complex to suppress the downstream targets. Additionally, genetic and pharmacologic inhibition of YAP disrupts the co-repressor complex to suppress the oncogenic activity of RAD21 and recapitulates the phenotypes of RAD21 depletion in HGSOC. Therefore, our work sheds light on the oncogenic role of frequent CNAs and identifies a previously unrecognized role of RAD21/YAP complex which contributes to tumorigenesis and chemo-resistance in HGSOC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193620 | GEO | 2023/04/10

REPOSITORIES: GEO

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Oncogenic RAD21 Amplification Coordinates with YAP/TEAD Transcriptional Co-Repressor Complex to Drive Tumorigenesis in High Grade Serous Ovarian Cancer

Project description:Ovarian cancer (OV) is the leading cause of mortality from gynaecological malignancies with poor prognosis and limited therapeutic options. Prevalent copy number alteration (CNA) is a genetic characteristic of OV, but its contribution to tumorigenesis remain unclear. Here, we identify RAD21, a component of the cohesin complex, as a frequently amplified and overexpressed oncogene in high grade serous ovarian cancer (HGSOC), the most common subtype of OV. RAD21 copy number amplification and overexpression are correlated with poor prognosis in HGSOC. In HGSOC cells and xenograft models, depletion of RAD21 inhibited cell proliferation by inducing mitotic phase arrest and thereby reducing tumour growth, whereas overexpression of RAD21 conferred resistance to carboplatin. Mechanistically, we found that RAD21 interacts with YAP/TEAD4 transcriptional co-repressors and recruits NuRD complex to suppress the downstream targets. Additionally, genetic and pharmacologic inhibition of YAP disrupts the co-repressor complex to suppress the oncogenic activity of RAD21 and recapitulates the phenotypes of RAD21 depletion in HGSOC. Therefore, our work sheds light on the oncogenic role of frequent CNAs and identifies a previously unrecognized role of RAD21/YAP complex which contributes to tumorigenesis and chemo-resistance in HGSOC.

2023-04-10 | GSE156845 | GEO

ECM-enriched proteomics of human fallopian tube, fimbria and ovarian tissue

Project description:We analysed the extracellular matrix (ECM) landscape of fresh, healthy tissues from human fallopian tube (FT), fimbria (FB, the tissue of origin of serous tubal intraepithelial lesions) and ovarian tissue (OV). The aim was to identify differentially expressed matrix proteins between FB and FT or OV which may promote the neoplastic transformation of serous tubal intraepithelial lesions (STICs) into high-grade serous ovarian cancer, HGSOC, and metastasis from the FB to the OV.

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Illumina HT-12 v4 expression array data for Ovarian Cancer Samples

Project description:This study aimed to generate a new panel of comprehensively, genomically characterized high-grade serous ovarian carcinoma (HGSOC) cell line and xenograft models. Multidimensional genomic data were generated and compared between cell lines/xenografts and the tumours they were derived from, indicating the cell lines/xenografts are highly similar to their patient-matched tumours. Cell line/xenograft data were also compared to TCGA ovarian tumours to show the cell lines are good models of clinical HGSOC. Illumina HT-12 v4 arrays were performed according to the manufacturer's directions on total RNA extracted from i) tumour cells purified from ovarian tumour ascites, and ii) established cell lines. Evaluation of the similarity in copy number/methylation/gene expression/mutational profiles of cell lines/tumours/xenografts was performed.

2016-08-11 | E-GEOD-71524 | biostudies-arrayexpress

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2016-08-11 | E-GEOD-71523 | biostudies-arrayexpress

Affymetrix SNP array data for Ovarian Cancer Samples

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2016-08-11 | E-GEOD-71522 | biostudies-arrayexpress

Transcriptomes of ex vivo grown spontaneous p53-R270H MYC murine ovarian and uterine cancers

Project description:Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment is understood. However, previous GEMMs of high-grade serous ovarian cancer (HGSOC) have had to utilize genetics rarely or never found in human HGSOC to yield ovarian cancer within the lifespan of a mouse. MYC, an oncogene, is amongst the most amplified genes in HGSOC, but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant negative mutant p53-R270H with a fallopian tube epithelium-specific promoter Ovgp1 to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 15.1 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium (FTE). Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate the Myc and Trp53-R270H transgene was able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology directed repair mutations. Histological and transcriptomic findings are consistent with the hypothesis that serous uterine cancer may originate from the fallopian tube epithelium.

2024-01-23 | GSE238158 | GEO

Netrin and its dependence receptors are mediators of high-grade serous ovarian cancer cell survival

Project description:We previously showed that DYRK1A is essential for ovarian cancer spheroid cell survival. DYRK1A regulates transcription by assembling the DREAM repressor complex and also regulates RNA polymerase II. However, the present understanding of how DYRK1A regulates transcription in high-grade serous ovarian cancer (HGSOC) spheroid cells to promote quiescence and survival is lacking. Here we performed GO-CRISPR screens in a panel of HGSOC spheroid cells in combination with transcriptional analyses of DYRK1A deficient spheroid cells. We identified netrin signaling components as essential factors of HGSOC spheroid cell survival. Netrin is well-characterized in axon development but has recently been implicated in other cancer types. We found that knockout of netrin ligands or receptors affects viability of spheroid cells. Netrin ligands and receptors are upregulated in HGSOC cells in suspension conditions. Together, this work suggests that the netrin signaling pathway may be a potential therapeutic target to specifically eliminate spheroid cells in HGSOC and highlights it as an important area requiring further investigation in the context of ovarian cancer.

2023-04-01 | GSE190294 | GEO

Gene signatures of normal hTERT immortalized ovarian epithelium and fallopian tube epithelium (paired cultures from 2 donor patients)

Project description:Most epithelial ovarian cancers are thought to arise from different cells in the ovarian or fallopian tube epithelium. We hypothesized that these distinct cells-of-origin may play a role in determining ovarian tumor phenotype and also could inform the molecular classification of ovarian cancer. To test this hypothesis, we developed new methods to isolate and culture paired normal human ovarian (OV) and fallopian tube (FT) epithelial cells from multiple donors without cancer and identified a cell-of-origin gene expression signature that distinguished these cell types within the same patient. Application of the OV versus FT cell-of-origin gene signature to gene expression profiles of primary ovarian cancers permitted identification of distinct OV and FT-like subgroups among these cancers. Importantly, the normal FT-like tumor classification correlated with a significantly worse disease-free survival. This work describes a new experimental method for culture of normal human OV and FT epithelial cells from the same patient. These findings provide new evidence that cell-of-origin is an important source of ovarian tumor heterogeneity and the associated differences in tumor phenotype.

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EZH2 Mediated Metabolic Rewiring Promotes High-grade Serous Ovarian Cancer Progression Independently of Histone Methyltransferase Activity II

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