Transcriptome profiling of organoids and tissues derived from murine oviductal and ovary surface epithelium (OSE) to study high-grade serous ovarian cancer (HG-SOC)
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ABSTRACT:
PROVIDER: PRJNA622465 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11464730_1.fastq.gz | Fastqsanger.gz | |||
| SRR11464730_2.fastq.gz | Fastqsanger.gz | |||
| SRR11464731_1.fastq.gz | Fastqsanger.gz | |||
| SRR11464731_2.fastq.gz | Fastqsanger.gz | |||
| SRR11464732_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Transcriptome profiling of organoids/tissues derived from murine oviduct and OSE was performed to study and compare the gene expression profiles in the both suspected origins of HG-SOC. CRISPR-Cas9 modified oviductal organoids (TBP clones, which were mutated in Trp53, Brca1 and Pten), the tumors derived upon xenotransplantation of the TBP-clones and subsequent tumor-derived organoids were additionally profiled to show the transcriptional change upon aquiring mutations and tumor development. Methods: Both oviductal and OSE organoids as well as oviductal TBP-clones and tumor-derived organoids were grown in Wnt-conditioned media prior harvesting for RNA extraction. Additionally, RNA was extracted from healthy oviductal and OSE tissues and Ovi-TBP-clone-derived tumor tissues. RNA was converted to cDNA and libraries were prepared using the CelSeq2 method and sequenced. Samples were sequenced on Illumina NextSeq500 by using 75-bp paired-end sequencing. Paired-end reads from Illumina sequencing were aligned to the mouse genome (GRCm38 assembly) by BWA. DESeq2 (v1.18.0) package was used for read normalization and differential expression analysis. Gene set enrichment analysis (GSEA) was performed using gene lists for motile cilium assembly against normalized RNA-seq reads of healthy oviductal an OSE organoids using GSEA software v3.0 beta2. GSEA was additionally used to detect enrichment of signature gene sets of different HG-SOC subtypes in the TBP-clone-derived murine tumors Results: Transcriptome analysis of oviductal and OSE organoids/tissues revealed tissue-specific gene expression pattern in the organoid systems. In contrast to OSE counterparts, oviductal organoids showed enrichment in motile cilium assembly genes, reflecting the presence of ciliated cells in this model. Results: Oviductal TBP-clones gave rise to different tumor phenotypes with distinct gene expression profiles. Analysis of the transcriptomes of these tumors divided the TBP-clone-derived tumors into two distinct HG-SOC molecular subtypes (differentiated- or immunoreactive-like subtypes), confirming the potential of organoids in modeling HG-SOC. Results: The tumor-derived organoids retained the distinct phenotypes observed in the originating Ovi-TBP-clone derived tumors. Subset of tumors showed epithelial and others mesenchymal features that were maintained in the respective organoid cultures also in the gene expression level. Conclusions: RNA sequencing showed tissue specific differences in murine oviductal and OSE organoids, and revealed HG-SOC-like features of oviductal mutants.
2020-05-04 | GSE147882 | GEO
Project description:The high-grade serous ovarian cancer (HG-SOC) tumor microenvironment (TME) is constellated by cellular elements and a network of soluble constituents that contribute to tumor progression. In the multitude of the secreted molecules, the endothelin-1 (ET-1) has emerged to be implicated in the tumor/TME interplay, however the molecular mechanisms induced by the ET-1-driven feed-forward loops (FFL) and associated with the HG-SOC metastatic potential need to be further investigated. The tracking of the patient-derived (PD) HG-SOC cell transcriptome by RNA-seq identified the vascular endothelial growth factor (VEGF) gene and its associated signature among those mostly upregulated by ET-1 and down-modulated by the dual ET-1R antagonist macitentan. Within the ligand-receptor pairs concurrently expressed in PD-HG-SOC cells, endothelial cells and activated fibroblasts, we discovered two intertwined FFL, the ET-1/ET-1R and VEGF/VEGF receptors, concurrently activated by ET-1 and shutting-down by macitentan, or by the anti-VEGF antibody bevacizumab. In parallel, we observed that ET-1 fine-tuned the tumoral and stromal secretome towards a pro-invasive pattern. Into the fray of the HG-SOC/TME double and triple co-cultures, the secretion of ET-1 and VEGF, that share a common co-regulation, was inhibited upon the administration of macitentan. Functionally, macitentan, mimicking the effect of bevacizumab, interfered with the HG-SOC/TME FFL-driven communication that fuel the HG-SOC invasive behaviour. The identification of ET-1 and VEGF FFL as tumor and TME actionable vulnerabilities, reveal how ET-1R blockade, targeting the HG-SOC cells and the TME simultaneously, may represent an effective therapeutic option for HG-SOC patients.
2024-07-17 | GSE268498 | GEO
Project description:High-grade serous ovarian cancer (HG-SOC), characterized by very frequent mutations in TP53 gene, is a highly lethal cancer and is refractory to therapeutic strategies. In HG-SOC, the reciprocal signal exchange between tumor cells and various types of stromal elements from the tumor microenvironment (TME) shapes the malignant phenotype and limits drug efficacy, suggesting that blunting the HG-SOC/TME interplay may improve the anti-tumor therapy response rate. Here, we unveil how the endothelin-1 (ET-1)/ET-1 receptors (ET-1R) signaling, instructing the mutual inter-regulation between HG-SOC cells, endothelial cells (EC) and activated fibroblasts, regulates malignant progression and PARP inhibitor (PARPi) response. Mechanistically, ET-1 axis, mimicking hypoxia, enhances the mutant p53 (mutp53)/YAP/hypoxia inducible factor-1α (HIF-1α) transcriptional cooperation, that culminates with the release of diffusible mediators, as ET-1 and VEGF, that charting a bilateral HG-SOC/stroma signaling route, regulate the acquisition of pro-metastatic traits and PARPi response. Concurrently, our study establishes that ET-1 signaling its instrumental for the activation of p53/YAP/HIF-1α transcriptional machinery within the EC and the activated fibroblasts, shaping their behaviour and secretome. The dual ET-1R antagonist macitentan, dismantling the ET-1R-mediated mutp53/YAP/HIF-1α network, interferes with the ET-1-guided tumor/stroma communication. In vivo macitentan, sensitizing HG-SOC patient-derived xenografts (PDX) to the PARPi, Olaparib, reduces their metastatic potential. Clinically relevant, ETAR/YAP/HIF-1α gene signature correlates with a dismal prognosis in HG-SOC patients. Our findings recognize in the networking between ET-1R and YAP/mutp53/HIF-1α a tumor/TME shared escaping strategy from DNA damaging agents and support the use of ET-1R antagonists in combinatorial treatments with PARPi for HG-SOC patients.
2023-01-11 | GSE196065 | GEO
Project description:The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) both considered candidates. Here, by using genetically engineered mouse models and organoids, we assessed the tumor-forming properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation and Tp53 mutation in Pax8+ FTE caused Serous Tubal Intraepithelial Carcinoma (STIC), which metastasized rapidly to the ovarian surface. These events were recapitulated by orthotopic injection of mutant FTE organoids. Engineering the same genetic lesions into Lgr5+ OSE or OSE-derived organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. FTE- and OSE-derived tumors had distinct transcriptomes, and comparative transcriptomics and genomics suggest that human HGSOC arises from both cell types. Finally, FTE- and OSE-derived organoids exhibited differential chemosensitivity. Our results comport with a dualistic origin for HGSOC and suggest that the cell-of-origin might influence therapeutic response.
2019-10-21 | GSE125016 | GEO
Project description:The transcription factor OCT4 orchestrates self-renewal gene expression signatures in embryonic stem cells and cancer cells. We show that OCT4 enhances HG-SOC aggressiveness by promoting the inactivation of the Retinoblastoma pathway and mediating mitotic stability by driving the expression of Chromosomal Passenger Complex in HG-SOC. Our data show that OCT4 has an unprecedented role in enforcing mitotic stability and controlling the RB tumorsuppressor pathway in human cancer cells.
2017-01-31 | GSE76689 | GEO
Project description:Medroxyprogesterone acetate inhibits tumorigenesis in mouse models of oviductal high-grade serous carcinoma
| PRJNA1336159 | ENA
Project description:The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH can be accurately measured when informed by the molecular signatures of the normal cells of origin. We surveyed the transcriptomes of ~ 4000 normal fallopian tube epithelial (FTE) cells, the cells of origin of serous ovarian cancer (SOC), and identified six FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH that was previously unrecognized. Importantly, NGH-based stratification of ~1700 tumors robustly predicted survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.
2020-01-10 | GSE132107 | GEO
Project description:Background/Objectives: Tubo-ovarian high-grade serous carcinoma (HGSC) is a highly lethal malignancy, usually diagnosed at an advanced stage due to the lack of early symptoms and biomarkers. Contraceptive hormone use is associated with reduced risk of HGSC, but the relative contributions of natural versus synthetic progestins, and their interaction with estrogens, are poorly characterized. Methods: We evaluated the chemopreventive efficacy of a synthetic progestin medroxyprogesterone acetate (MPA), progesterone (P4), and combined 17β-estradiol-progesterone (E2+P4) in a well-characterized genetically engineered mouse model (GEMM) of oviductal HGSC based on conditional inactivation of one or both alleles of the Brca1, Trp53, Rb1, and Nf1 tumor suppressor genes (BPRN-het and BPRN-homo mice, respectively). Mice received hormones or placebo via slow-release pellets implanted subcutaneously, and after induction of tumor formation, mice were monitored for tumor development, progression, and survival. Tumor incidence was assessed histologically, and hormone effects were further explored via RNA-seq analysis of oviductal tissues. Results: MPA significantly reduced HGSC incidence and delayed tumor progression compared to placebo, P4, and P4 + E2, in both BPRN-homo and BPRN-het mice, with up to 78% tumor-free survival in the MPA-treated BPRN-het cohort. P4 monotherapy did not provide significant protection vs. placebo, while the E2+P4 combination accelerated tumorigenesis and reduced survival (p < 0.0001 in BPRN-homo and p = 0.0004 in BPRN-het mice). MPA did not affect tumorigenesis in a colon cancer GEMM, or the growth of mouse HGSC-derived cells in vivo, suggesting a role for MPA in the early stages of HGSC development. Gene expression analyses showed that P4 and MPA downregulated cholesterol homeostasis, early and late estrogen response, and epithelial-mesenchymal transition pathways, though only MPA translated this into substantial tumor protection. Conclusions: These findings demonstrate that a synthetic progestin, specifically MPA, confers robust protection against HGSC development, while P4 is not effective and a combination including E2 increases risk. This work also illustrates how HGSC GEMMs can be used to compare the chemopreventive effects of various synthetic progestins on HGSC development in order to prioritize the most effective ones for use in preventing HGSC in high-risk populations.
2025-12-04 | GSE309487 | GEO
Project description:To demonstrate the use of a whole-genome oligonucleotide array to perform expression profiling on a series of microdissected late-stage, high-grade papillary serous ovarian adenocarcinomas to establish a prognostic gene signature correlating with survival and to identify novel survival factors in ovarian cancer. Advanced stage papillary serous tumors of the ovary are responsible for the majority of ovarian cancer deaths, yet the molecular determinants modulating patient survival are poorly characterized. We identify and validate a prognostic gene expression signature correlating with survival in a series of microdissected serous ovarian tumors. Experiment Overall Design: We identified 53 advanced stage, high-grade primary tumor specimens and 10 normal ovarian surface epithelium (OSE) brushings.
2009-10-23 | E-GEOD-18520 | biostudies-arrayexpress
Project description:Ovarian cancer is the fifth leading cause of cancer death among US women. Evidence supports the hypothesis that high-grade serous ovarian cancers (HGSC) may originate in the distal end of the fallopian tube. Although a heterogeneous disease, 96% of HGSC contain mutations in p53. In addition, the “p53 signature”, or overexpression of p53 protein (usually associated with mutation), is a potential precursor lesion of fallopian tube derived HGSC suggesting an essential role for p53 mutation in early serous tumorigenesis. To further clarify p53-mutation dependent effects on cells, murine oviductal epithelial cells (MOE) were stably transfected with a construct encoding for the R273H DNA binding domain mutation in p53, the most common mutation in HGSC. Mutation in p53 was not sufficient to transform MOE cells, but did significantly increase cell migration. A similar p53 mutation in murine ovarian surface epithelium (MOSE), another potential progenitor cell for serous cancer, was not sufficient to transform the cells nor change migration suggesting tissue specific effects of p53 mutation. Microarray data confirmed expression changes in pro-migratory genes in p53R273H MOE compared to parental cells, which could be reversed by suppressing Slug expression. Combining p53R273H with KRASG12V activation caused transformation of MOE into high-grade sarcomatoid carcinoma when xenografted into nude mice. Elucidating the specific role of p53R273H in the fallopian tube will improve understanding of changes at the earliest stage of transformation and could help develop chemopreventative strategies to prevent the accumulation of additional mutations and reverse progression of the “p53 signature” thereby, improving survival rates. We used a microarray to determine global changes in gene expression as a result of the p53 mutation specifically in mouse oviductal epithelium. Murine oviductal cells (MOE) were obtained from Dr. Barbara Vanderhyden at the University of Ottawa. Stable cell lines were generated using antibiotic resistant plasmids containing p53 R273H (Addgene, plasmid: 16439, donated by Dr. Vogelstein, Johns Hopkins University school of Medicine, Baltimore, MD) or pCMV-Neo (Origene PCMV6XL4, Rockville, MD). Total RNA was extracted from cell pellets collected from consecutive passages.
2014-10-25 | E-GEOD-62694 | biostudies-arrayexpress