Ovarian Granulosa Cell Tumor Sequencing Project Data Access Committee
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PROVIDER: EGAC00001000841 | EGA |
REPOSITORIES: EGA
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Project description:The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation.
| S-EPMC4484779 | biostudies-literature
Project description:The Genetic Association Information Network (GAIN) Data Access Committee was established in June 2007 to provide prompt and fair access to data from six genome-wide association studies through the database of Genotypes and Phenotypes (dbGaP). Of 945 project requests received through 2011, 749 (79%) have been approved; median receipt-to-approval time decreased from 14 days in 2007 to 8 days in 2011. Over half (54%) of the proposed research uses were for GAIN-specific phenotypes; other uses were for method development (26%) and adding controls to other studies (17%). Eight data-management incidents, defined as compromises of any of the data-use conditions, occurred among nine approved users; most were procedural violations, and none violated participant confidentiality. Over 5 years of experience with GAIN data access has demonstrated substantial use of GAIN data by investigators from academic, nonprofit, and for-profit institutions with relatively few and contained policy violations. The availability of GAIN data has allowed for advances in both the understanding of the genetic underpinnings of mental-health disorders, diabetes, and psoriasis and the development and refinement of statistical methods for identifying genetic and environmental factors related to complex common diseases.
| S-EPMC3617375 | biostudies-literature
Project description:Granulosa cell tumors (GCT) are rare ovarian malignancies. Due to the lack of effective treatment in late relapse, there is a clear unmet need for novel therapies. Forkhead Box L2 (FOXL2) is a protein mainly expressed in granulosa cells (GC) and therefore is a rational therapeutic target. Since we identified tumor infiltrating lymphocytes (TILs) as the main immune population within GCT, TILs from 11 GCT patients were expanded, and their phenotypes were interrogated to determine that T cells acquired late antigen-experienced phenotypes and lower levels of PD1 expression. Importantly, TILs maintained their functionality after ex vivo expansion as they vigorously reacted against autologous tumors (100% of patients) and against FOXL2 peptides (57.1% of patients). To validate the relevance of FOXL2 as a target for immune therapy, we developed a plasmid DNA vaccine (FoxL2-tetanus toxin; FoxL2-TT) by fusing Foxl2 cDNA with the immune-enhancing domain of TT. Mice immunization with FoxL2-TT controlled growth of FOXL2-expressing ovarian (BR5) and breast (4T1) cancers in a T cell-mediated manner. Combination of anti-PD-L1 with FoxL2-TT vaccination further reduced tumor progression and improved mouse survival without affecting the female reproductive system and pregnancy. Together, our results suggest that FOXL2 immune targeting can produce substantial long-term clinical benefits. Our study can serve as a foundation for trials testing immunotherapeutic approaches in patients with ovarian GCT.
| S-EPMC7455139 | biostudies-literature
Project description:The spontaneous development of juvenile-onset, ovarian granulosa cell (GC) tumors in the SWR/Bm (SWR) inbred mouse strain is a model for juvenile-type GC tumors that appear in infants and young girls. GC tumor susceptibility is supported by multiple Granulosa cell tumor (Gct) loci, but the Gct1 locus on Chr 4 derived from SWR strain background is fundamental for GC tumor development and uniquely responsive to the androgenic precursor dehydroepiandrosterone (DHEA). To resolve the location of Gct1 independently from other susceptibility loci, Gct1 was isolated in a congenic strain that replaces the distal segment of Chr 4 in SWR mice with a 47 × 10(6)-bp genomic segment from the Castaneus/Ei (CAST) strain. SWR females homozygous for the CAST donor segment were confirmed to be resistant to DHEA- and testosterone-induced GC tumorigenesis, indicating successful exchange of CAST alleles (Gct1 ( CA )) for SWR alleles (Gct1 ( SW )) at this tumor susceptibility locus. A series of nested, overlapping, congenic sublines was created to fine-map Gct1 based on GC tumor susceptibility under the influence of pubertal DHEA treatment. Twelve informative lines have resolved the Gct1 locus to a 1.31 × 10(6)-bp interval on mouse Chr 4, a region orthologous to human Chr 1p36.22.
| S-EPMC3560948 | biostudies-literature
Project description:RNA was extracted from normal human granulosa cells from IVF patients (hGC1 and hGC2 samples) and from adult-type ovarian granulosa cell tumor samples (H1, H8, H20, H23, H24, H28, H30, H33, H4, H18) as described in Jamieson et al, 2010. RNA from all samples was linearly amplified using the Whole Transcriptome Amplification kit (Sigma), starting from 300ng of RNA, and with 12 amplifications cycles. cDNA was purified on columns and sent to the Nimblegen platform for hybridization and transcriptional profiling. The FOXL2 locus was gentoyped in tumor samples, and all samples were found positive for the recurrent somatic mutation p.Cys134Trp which is present in >95% of adult-type ovarian granulosa cell tumors (Shah et al, 2009).
2012-08-02 | E-MTAB-483 | biostudies-arrayexpress
Project description:Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. After read alignment and quality-control filtering, DESeq2 was used to identify differentially expressed genes (DEG) between primary and recurrent tumors. Functional enrichment pathway analysis and gene set enrichment analysis was performed using "clusterProfiler" and "GSVA" R packages. TME composition was investigated through the analysis and integration of multiple published RNA-seq deconvolution algorithms. TME analysis results were externally validated using data from independent previously published RNA-seq datasets. A total of 31 DEGs were identified between primary and recurrent aGCTs. These included genes with known function in hormone signaling such as LHCGR and INSL3 (more abundant in primary tumors) and CYP19A1 (more abundant in recurrent tumors). Gene set enrichment analysis revealed that primarily immune-related and hormone-regulated gene sets expression was increased in recurrent tumors. Integrative TME analysis demonstrated statistically significant depletion of cancer-associated fibroblasts in recurrent tumors. This finding was confirmed in multiple independent datasets.ImplicationsRecurrent aGCTs exhibit alterations in hormone pathway gene expression as well as decreased infiltration of cancer-associated fibroblasts, suggesting dual roles for hormonal signaling and TME remodeling underpinning disease relapse.
| S-EPMC10150241 | biostudies-literature
Project description:The 1,000 plants (1KP) project is an international multi-disciplinary consortium that has generated transcriptome data from over 1,000 plant species, with exemplars for all of the major lineages across the Viridiplantae (green plants) clade. Here, we describe how to access the data used in a phylogenomics analysis of the first 85 species, and how to visualize our gene and species trees. Users can develop computational pipelines to analyse these data, in conjunction with data of their own that they can upload. Computationally estimated protein-protein interactions and biochemical pathways can be visualized at another site. Finally, we comment on our future plans and how they fit within this scalable system for the dissemination, visualization, and analysis of large multi-species data sets.
| S-EPMC4306014 | biostudies-literature
Project description:Although angiogenesis has been proposed as a therapeutic target for the treatment of ovarian granulosa cell tumor (GCT), its potential has not been evaluated in controlled studies. To do so, we used the Pten (tm1Hwu/tm1Hwu); Ctnnb1 (tm1Mmt/+);Amhr2 (tm3(cre)Bhr/+) (PCA) mouse model, which develops GCTs that mimic the advanced disease in women. A monoclonal anti-vascular endothelial growth factor A (VEGFA) antibody was administered weekly to PCA mice beginning at 3 weeks of age. By 6 weeks of age, anti-VEGFA therapy significantly decreased tumor weights relative to controls (P < .05) and increased survival, with all treated animals but none of the controls surviving to 8 weeks of age. Analyses of PCA tumors showed that anti-VEGFA treatment resulted in significant decreases in tumor cell proliferation and microvessel density relative to controls (P < .05). However, treatment did not have a significant effect on apoptosis or tumor necrosis. The VEGFA receptor 2 (VEGFR2) signaling effector p44/p42 mitogen-activated protein kinase (MAPK), whose activity is associated with cell proliferation, was significantly less phosphorylated (i.e., activated) in tumors from the treated group (P < .05). Conversely, no significant difference was found in the activation of protein kinase B, a VEGFR2 signaling effector associated with cell survival. Together, these results suggest that anti-VEGFA therapy is effective at inhibiting GCT growth in the PCA model and acts by reducing microvascular density and cell proliferation through inhibition of the VEGFR2-MAPK pathway. Findings from this preclinical model therefore support the investigation of targeting VEGFA for the adjuvant treatment of GCT in women.
| S-EPMC3660791 | biostudies-literature
Project description:Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-κB) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to IκB degradation and activation of NF-κB. NF-κB activation was confirmed by nuclear localization of NF-κB p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-κB signaling attenuated LPS-induced TNFα plus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-κB signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-κB does not sensitize GCTs to TRAIL or cisplatin.
| S-EPMC3118942 | biostudies-literature
Project description:PurposeWe investigated the interactions between mural granulosa cells (MGCs) and cumulus granulosa cells (CGCs) during ovulation after the LH surge.MethodsWe performed clustering, pseudotime, and interactome analyses utilizing reported single-cell RNA sequencing data of mouse ovary at 6 h after eCG-hCG injection.ResultsClustering analysis classified granulosa cells into two distinct populations, MGCs and CGCs. Pseudotime analysis divided granulosa cells into before and after the LH surge, and further divided them into two branches, the ovulatory MGCs and the ovulatory CGCs. Interactome analysis was performed to identify the interactions between MGCs and CGCs. Twenty-six interactions were acting from CGCs toward MGCs, involving ovulation and steroidogenesis. Thirty-six interactions were acting from MGCs toward CGCs, involving hyaluronan synthesis. There were 25 bidirectional interactions, involving the EGFR pathway. In addition, we found three novel interactions: Ephrins-Ephs pathway and Wnt-Lrp6 pathway from CGCs to MGCs, associated with steroidogenesis and lipid transport, respectively, and TGF-β-TGFBR1 pathway from MGCs to CGCs, associated with hyaluronan synthesis.ConclusionsMGCs and CGCs interact with each other in the preovulatory follicle after the LH surge, and their interactions have roles in corpus luteum formation, oocyte maturation, and follicle rupture.
| S-EPMC10867398 | biostudies-literature