Comparison of gene expression in tumor ovarian surface epithelial cells with different p53 status
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE65206 | GEO | 2016/02/03
SECONDARY ACCESSION(S): PRJNA273401
REPOSITORIES: GEO
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Project description:Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. On the basis of its histopathology and molecular-genomic changes ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC-xenografts that recapitulate the molecular and biological heterogeneity of human ovarian cancer. Thirty-four EOC-xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient-derived EOC-xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor-specific molecular markers and develop novel treatment modalities.
2015-01-07 | GSE56920 | GEO
Project description:Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. On the basis of its histopathology and molecular-genomic changes ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC-xenografts that recapitulate the molecular and biological heterogeneity of human ovarian cancer. Thirty-four EOC-xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient-derived EOC-xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor-specific molecular markers and develop novel treatment modalities. EOC-xenografts collected from subcutis, abdominal masses and ascitic fluid of mice engrafted with tumors at different passages (from 1 to 6) and from patient specimens, underwent one-color microarray-based gene expression profiling. To assess the amount of human- and mouse-derived cells in the xenograft tumors, total RNA was evaluated by species specific qPCR assays for beta actin. Only samples with a human RNA content > 75% were analyzed. Nine patient specimens and 62 xenograft samples (representing 29 EOC-xenograft models) underwent gene expression analysis with SurePrint G3 Human GE V2 8x60K microarrays.
2015-01-07 | E-GEOD-56920 | biostudies-arrayexpress
Project description:Background: The expression of MDM4, a well-known p53-inhibitor, is positively associated with chemotherapy response and overall survival in epithelial ovarian cancer (EOC). The basis of this association remains elusive. Since the occurrence of metastasis is one of the factors responsible for the high death rate of this cancer, we analyzed MDM4 involvement in EOC metastatic process. Methods: In vivo and in vitro models, based on 2D and 3D assays, were employed to assess the activity of MDM4 in ovarian cancer progression. A 3D-bioprinting co-culture system was ad hoc developed for this study. Proteomic analysis was conducted on 3D multicellular tumour spheroids to assess pathways triggered by MDM4 overexpression. Results: In mouse models, increased MDM4 reduced intraperitoneal dissemination of human and murine EOC cells, independently of p53 and in a cell-autonomous way. Consistently, high MDM4 correlates with increased overall survival probability in large public data sets. 2D and 3D assays indicated that MDM4 impairs the early steps of the metastatic process. The 3D-bioprinting co-culture system showed reduced dissemination and intravasation into vessel-like structures of MDM4-expressing cells. Proteomic analysis of EOC spheroids revealed that MDM4 reduces protein synthesis and decreases mTOR signaling. Accordingly, MDM4 did not further inhibit EOC cell migration when its activity towards mTOR is blocked genetically or pharmacologically. Conversely, increased MDM4 reduced the efficacy of mTOR inhibitors in constraining EOC cell migration. Conclusions: Overall, these data clarify the antagonism of MDM4 towards EOC progression and suggest the usefulness of MDM4 assessment for tailored application of mTOR targeted therapy.
2021-05-27 | PXD019935 | Pride
Project description:Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histological sub-type remains undetermined. While these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors. Methods: To explore the spectrum of genomic alterations common to mucinous tumors we performed high resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n=20) and borderline tumors (n=22). Results: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors. Conclusions: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors performed to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways. Copy number data was generated for 42 mucinous ovarian tumours (20 benign, 22 borderline). Epithelial and stromal DNA from the tumours and matched-normal lymphocyte DNA were all analysed. Processed/normalized data for the germline DNA samples are not provided because they themselves are normalised to a diploid copy number, making all the probe values 2, which is not informative.
2012-08-26 | E-GEOD-39076 | biostudies-arrayexpress
Project description:Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histological sub-type remains undetermined. While these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors. Methods: To explore the spectrum of genomic alterations common to mucinous tumors we performed high resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n=20) and borderline tumors (n=22). Results: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors. Conclusions: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors performed to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways.
2012-08-26 | GSE39076 | GEO
Project description:Ovarian cancer is the most lethal gynecological malignancy in the western world. Despite recent efforts to characterize ovarian cancer using molecular profiling, few targeted treatment options are currently available. Here, we examined genetic variants, fusion transcripts, SNP genotyping, and gene expression patterns for early-stage (I, II) ovarian carcinomas (n=96) in relation to clinicopathological characteristics and clinical outcome, thereby identifying novel genetic features of ovarian carcinomas. Furthermore, mutation frequencies of specific genetic variants and/or their gene expression patterns were associated with histotype and overall survival, e.g. SLC28A2 (mucinous ovarian carcinoma histotype), ARCN1 (low expression in 0-2 year survival group), and tumor suppressor MTUS1 (mutation status and overall survival). The long non-coding RNA MALAT1 was identified as a highly promiscuous fusion transcript in ovarian carcinoma. Moreover, gene expression deregulation for 23 genes was associated with tumor aggressiveness. Taken together, the novel biomarkers identified here may improve ovarian carcinoma subclassification and patient stratification according to histotype and overall survival.
2018-10-04 | GSE101107 | GEO
Project description:Ovarian cancer is the most lethal gynecological malignancy in the western world. Despite recent efforts to characterize ovarian cancer using molecular profiling, few targeted treatment options are currently available. Here, we examined genetic variants, fusion transcripts, SNP genotyping, and gene expression patterns for early-stage (I, II) ovarian carcinomas (n=96) in relation to clinicopathological characteristics and clinical outcome, thereby identifying novel genetic features of ovarian carcinomas. Furthermore, mutation frequencies of specific genetic variants and/or their gene expression patterns were associated with histotype and overall survival, e.g. SLC28A2 (mucinous ovarian carcinoma histotype), ARCN1 (low expression in 0-2 year survival group), and tumor suppressor MTUS1 (mutation status and overall survival). The long non-coding RNA MALAT1 was identified as a highly promiscuous fusion transcript in ovarian carcinoma. Moreover, gene expression deregulation for 23 genes was associated with tumor aggressiveness. Taken together, the novel biomarkers identified here may improve ovarian carcinoma subclassification and patient stratification according to histotype and overall survival.
2018-10-04 | GSE101108 | GEO
Project description:We compared miRNAs expression in mucinous ovarian cancer cell between treated with siPRKRA and contrl siRNA. We hypothesize that PRKRA regulates chemosensitivity in mucinous ovarian cancer. Therefore, we aim to idetify the PRKRA-mediated miRNA which regulate chemosensitivity in mucinous ovarian cancer.
2019-01-01 | GSE119845 | GEO
Project description:Esophageal cancer is one of the most common cancers where TP53 is mutated frequently. Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer, and is one of the most lethal cancers worldwide. ESCC evolves often to lung metastasis, which is associated with a dismal prognosis. P53R175H (homologous to Trp53R172H in mice) is a common hot spot mutation. How metastasis is regulated by p53R175H in ESCC, or cancers in general, remains to be elucidated. To investigate p53R175H mediated molecular mechanisms, we utilized germline Trp53R172H/- mice, and generated esophageal specific Trp53-/- mice and Trp53+/+ mice treated with the 4-NQO esophageal-specific carcinogen (a common exposure in humans) to model ESCC. In the primary Trp53R172H/- tumor cell lines established from these mouse models, we depleted Trp53R172H (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, to understand the molecular basis for mutant p53 driven lung metastasis, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We performed Gene Set Enrichment Analysis (GSEA) and identified the YAP-BIRC5 axis as a potential mediator of Trp53R172H mediated metastasis. As a target gene of YAP, BIRC5 encodes an anti-apoptotic protein, namely survivin. We demonstrate that survivin expression increases in the presence of Trp53R172H but not wild-type Trp53. Furthermore, depletion of survivin decreases Trp53R172H driven lung metastasis. Mechanistically, Trp53R172H but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce survivin expression. Furthermore, survivin high expression level is associated with increased metastasis in several GI cancer, suggesting that survivin may be a key regulator to metastasis. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.
2020-12-01 | GSE143696 | GEO
Project description:Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1-3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rbf/f) in mice did not affect pancreatic exocrine cells, the α-cell/β-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated PanNET with a Ki67-labeling index of 2.7%. In contrast, pancreas-specific induction of a p53 mutation (Pdx1-Cre;Trp53R172H) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre;Trp53R172H;Rb f/f) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53R172H;Rb f/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET.
2020-06-17 | GSE152582 | GEO