Transcriptomes of ex vivo grown spontaneous p53-R270H MYC murine ovarian and uterine cancers
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PROVIDER: PRJNA998063 | ENA |
REPOSITORIES: ENA
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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.
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Project description:Ineffective endometrial matrix remodeling, a key factor in infertility, impedes embryo implantation in the uterine wall. Our study reveals the cellular and molecular impact of human collagenase-1 administration in mouse uteri, demonstrating enhanced embryo implantation rates. Collagenase-1 promotes remodeling of the endometrial extracellular matrix (ECM), degrading collagen fibers and proteoglycans. This process releases matrix-bound bioactive factors, (e.g. VEGF, decorin), facilitating vascular permeability and angiogenesis. Collagenase-1 elevates embryo implantation regulators, including NK cell infiltration and the key cytokine LIF. Remarkably, uterine tissue maintains structural integrity despite reduced endometrial collagen fiber tension. In-utero collagenase-1 application rescues implantation in the heat stress and embryo transfer models, known for low implantation rates. Importantly, ex-vivo exposure of human uterine tissue to collagenase-1 induces collagen de-tensioning and VEGF release, mirroring remodeling observed in mice. Our research highlights collagenase potential to induce and orchestrate cellular and molecular processes enhancing uterine receptivity for effective embryo implantation. This innovative approach underscores ECM remodeling mechanisms critical for embryo implantation
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Project description:Expression profiling of thymic lymphomas derived from HIF1a+/+, p53R270H/R270H; HIF1a+/-, p53R270H/R270H; and HIF1aKI/+, p53R270H/R270H mice. HIF1a and HIF2a share a high degree of sequence homology, but recent work has shown that the two a subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIFa subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2a expression and Hif1a+/- mice to homozygotes for the R270H mutation in p53. Heterozygosity for Hif1a significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1a levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, Dtx1 and Nrarp. Keywords: genetic modification, disease state analysis Thymic lymphoma tissue was preserved at the time mice were sacrificed. 4-5 samples from each of 3 genotypes (HIF1a+/-, p53R270H/R270H, HIF1aKI/+; p53R270H/R270H; and HIF1a+/+, p53R270H/R270H) were then used for microarray analysis to identify differences in gene expression that could account for changes in tumor onset and incidence.
2009-01-12 | E-GEOD-14336 | biostudies-arrayexpress
Project description:Expression profiling of thymic lymphomas derived from HIF1a+/+, p53R270H/R270H; HIF1a+/-, p53R270H/R270H; and HIF1aKI/+, p53R270H/R270H mice. HIF1a and HIF2a share a high degree of sequence homology, but recent work has shown that the two a subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIFa subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2a expression and Hif1a+/- mice to homozygotes for the R270H mutation in p53. Heterozygosity for Hif1a significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1a levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, Dtx1 and Nrarp. Keywords: genetic modification, disease state analysis
2009-01-12 | GSE14336 | GEO
Project description:The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in normal and cancer tissue from the uterine cervix. There are a total of 63 samples, 15 samples of normal histology and 48 cervical cancers. The normal cervical samples were from women who underwent a hysterectomy for uterine fibroids. The 48 cervical cancers were from women who were treated at the Innsbruck Medical University between 1990 and 2006. Bisulphite converted DNA from the 63 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2012-02-23 | E-GEOD-30759 | biostudies-arrayexpress
Project description:The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in normal and cancer tissue from the uterine cervix. There are a total of 63 samples, 15 samples of normal histology and 48 cervical cancers. The normal cervical samples were from women who underwent a hysterectomy for uterine fibroids. The 48 cervical cancers were from women who were treated at the Innsbruck Medical University between 1990 and 2006.
2012-02-23 | GSE30759 | GEO
Project description:Tamoxifen treatment in breast cancer patients increases their risk of developing uterine cancer that is more likely of poor prognosis. However, the exact mechanism leading to this increased and the worse outcomeendometrial cancer risk following tamoxifen exposure are still unknown, and effective preventive strategies are lacking. To address this question, we performed whole-exome sequencing of 21 (discovery cohort) and digital droplet PCR for 40 (validation cohort ) tamoxifen-associated uterine cancers. We identified genomic features that have been previously reported for uterine cancer, including recurrent mutations in PTEN, KRAS, TP53 and ARIDA1 and copy number alterations in the RTK and PI3K pathway. However, we also found that tamoxifen-associated uterine cancers have a substantially low frequency of PIK3CA and PIK3R1 mutations, the most prevalent mutations in non-tamoxifen-associated uterine cancers. Moreover, overall survival is significantly worse in uterine tumors without PIK3CA mutations, which could explain the observed poor prognosis in tamoxifen-associated uterine cancers . We also performed in vivo studies of normal uterine tissue and show that tamoxifen activates the PI3Kinase pathway and increases proliferation that in turn is abrogated by the PI3Kinase inhibitor, alpelisib. Together, this study uncovers the unique molecular profile of tamoxifen-associated uterine cancer and , offers mechanistic insights in the observed increase in endometrial cancer risk following tamoxifen treatment and a potential preventive approach. Moreover, we here describe for the first time a new general principle that a drug, as a side effect, can activate a pathway which would otherwise only be activated if a somatic mutation would have occurred thereby mimicking the effect of a driver mutation for cancer.
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2022-10-15 | PXD032405 | Pride