Distinct transcriptional programs of ascitic and solid cancer cells induce a different response to chemotherapy in high-grade serous ovarian cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE201047 | GEO | 2022/07/06
REPOSITORIES: GEO
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Project description:High grade serous ovarian carcinoma (HGSOC) accounts for ~70% of ovarian cancer cases. Non-invasive, highly specific blood-based tests for pre-symptomatic screening in women are crucial to reducing the mortality associated with this disease. Since most HGSOCs typically arise from the fallopian tubes (FT), our biomarker search focused on proteins found on the surface of extracellular vesicles (EVs) released by both FT and HGSOC tissue explants and representative cell lines. Using mass spectrometry, 985 EV proteins (exo-proteins) were identified that comprised the FT/HGSOC EV core proteome. Transmembrane exo-proteins were prioritized because these could serve as antigens for capture and/or detection. With a nano-engineered microfluidic platform, six newly discovered exo-proteins (ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF) plus a known HGSOC associated protein, FOLR1 exhibited classification performance ranging from 85-98% in a case-control study using plasma samples representative of early (including stage IA/B) and late stage (stage III) HGSOCs. Furthermore, by a linear combination of IGSF8 and ITGA5 based on logistic regression analysis, we achieved a sensitivity of 80% with 99.8% specificity and a positive predictive value of 13.8%. Importantly, these exo-proteins also can accurately discriminate between ovarian and 12 types of cancers commonly diagnosed in women. Our studies demonstrate that these lineage-associated exo-biomarkers can detect ovarian cancer with high specificity and sensitivity early and potentially while localized to the FT when patient outcomes are more favorable.
2023-10-09 | PXD036726 | Pride
Project description:High grade serous ovarian cancer (HGSOC) is characterized by late stage, rapid progression, easy drug resistance, high mortality and recurrence rate. Tubal secretory cells have always been considered as the origin cells of HGSOC, due to the high heterogeneity of the latter, the type and mechanism of cell origin is poorly confirmed. Combined with single-nuclei RNA sequencing (snRNA-seq) and Bulk tissue transcriptome sequencing, we expounded the composition of epithelial cell subgroups of fallopian tubes and HGSOCs.
2023-12-31 | GSE223426 | GEO
Project description:Despite the similar histologic appearances of high-grade serous ovarian cancers (HGSOCs), clinical observations point to marked differences in their gross appearances. Some patients have numerous small nodules, whereas others have bulkier disease; some patients have widespread disease, whereas others have more localized disease. However, a systematic framework for classifying such gross morphologic differences does not exist. The implementation of a laparoscopic triage algorithm for patients with advanced HGSOC enabled us to prospectively obtain detailed video images of HGSOC that could be analyzed to identify morphologic subtypes. In this study, we aimed to develop and characterize a gross morphologic classification system for HGSOC. Specifically, we assessed whether HGSOC can be reliably divided into distinct gross morphologic subtypes and whether such subtypes have different clinical outcomes and molecular features.
2023-01-27 | PXD031518 | Pride
Project description:Purpose：Forkhead box M1 (FOXM1) transcription factor is ubiquitously expressed in embryonic tissues but rare in differentiated cells. Increased expression of FOXM1 is observed in a variety of human malignancies. Here, we sought to characterize the expression and tumorigenic roles of FOXM1 in high-grade serous ovarian carcinoma (HGSOC). Experimental Design：TCGA dataset were analyed to identify potential master transcriptional regulators in HGSOC. Immunohistochemistry was performed to evaluate the clinical significance of FOXM1 in HGSOC. Invasion, clonogenic assays were conducted to determine to functional role of FOXM1. ChIP-seq and luciferase analyses were utilized to identify FOXM1 direct target genes in HGSOC. Association between mutant p53 and FOXM1 expression was investigated through TCGA data analysis, immunohistochemistry stainingand western blot. Results: We identified FOXM1 as a potential key transcription factor in ovarian cancer. FOXM1 was markedly increased in HGSOCs and high FOXM1 expression correlated with poor prognosis in HGSOC patients. Mechanistically, FOXM1 regulated CCNF and KIF20A at transcriptional level through binding on their promoters. Consistently, CCNF and KIF20A were elevated in HGSOCs and correlated with poor prognosis. Importantly, mutant p53 contribute to the high expression of FOXM1 in HGSOCs. Conclusions: These data reveal FOXM1 as a driver oncogenic transcription factor that promotes ovarian cancer malignancy which might be a potential drug target in HGSOC.
2021-12-01 | GSE142567 | GEO
Project description:Gene expression-based molecular subtypes of high grade serous tubo-ovarian cancer (HGSOC) are distinguished by differential immune and stromal infiltration and may provide opportunities for the development of targeted therapies. Integration of molecular subtypes into clinical trials has been hindered by inconsistent subtyping methodology. Adopting two independent approaches, we derived and internally validated algorithms for molecular subtype prediction from gene-expression array data in 1650 tumors. We applied resulting models to assign labels to 3829 HGSOCs from the Ovarian Tumor Tissue Analysis (OTTA) consortium evaluated on NanoString. Using the labeled NanoString data, we developed, confirmed, and validated a clinical-grade test and prediction tool. We also used the OTTA dataset to evaluate associations between molecular subtype, biological, and clinical features. A gene expression study from the Ovarian Tumor Tissue Analysis (OTTA) consortium
2020-07-22 | GSE135820 | GEO
Project description:To improve our understanding of the molecular basis of chemo-refractory high grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two independent validation cohorts (spanning four academic centers) and utilizing two biospecimen types (formalin-fixed paraffin-embedded and frozen tumor biopsies). As the largest and most comprehensive study of refractory ovarian cancers to date, this effort identified a 64-protein signature that predicts a subset of HGSOCs refractory to initial platinum-based therapy with high specificity and is validated in two independent patient cohorts. We also detected significant association between lack of Ch17 loss-of-heterozygosity and refractory disease. Moreover, based on protein pathway expression, five novel clusters of HGSOC were identified and validated across two independent patient cohorts, as well as in patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic targets.
2023-09-18 | PXD040742 | panorama
Project description:High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic neoplasm, with five-year survival rate below 30%. Early disease detection is of utmost importance to improve the cure rate of HGSOC. Liquid biopsies are now becoming a new paradigm to develop novel biomarkers with diagnostic and prognostic purposes. The focus of this study was to detect the levels of circulating miRNAs in tissues and sera from patients with HGSOC and to evaluate their diagnostic value. To this end, an array-based discovery platform, followed by an innovative statistical approach of data normalization, was exploited, to identify miRNA species selectively expressed in serum of patients with HGSOC. Sera from 106 high grade serous ovarian carcinoma (HGSOC) and 24 healthy controls were used for profiling serum microRNA using a modified version of a commercially available microarray, with the aim of identifying differentially expressed microRNA between tumor patients and healthy controls.
2017-01-30 | E-MTAB-4667 | biostudies-arrayexpress
Project description:Ovarian cancer is one of the most common gynecologic malignancies globally, which is a significant cause of morbidity and mortality, accounting for 207,252 new deaths each year. The 5-year survival rate of this cancer is reported to be 26-42% and is often diagnosed in an advanced stage. Epithelial ovarian cancer (EOC) is a heterogeneous disease that comprises various histological subtypes. Of them, high-grade serous ovarian cancer (HGSOC) is the most common cancer subtype (70-80%), which is highly aggressive and grows rapidly. Despite the initial success observed with cytoreductive surgery and platinum-based chemotherapy, over 75% of HGSOC patients experience relapse following completion of first-line therapy. The challenge of tailoring therapeutic interventions to control progressive disease is compounded by the inherent cellular heterogeneity and genomic instability characteristic of HGSOC. While platinum chemotherapy remains the cornerstone of contemporary treatment, the grim reality persists that a majority of EOC patients develop chemotherapy resistance, resulting in a five-year survival rate of less than 50%. Numerous ovarian cancer studies have underscored the prognostic significance of factors such as age at diagnosis, disease stage, grade, histology, residual disease post-surgery, and disease recurrence. The genetic predisposition towards EOC indicates that high-grade HGSC exhibits significant chromosomal instability and carries mutations in the tumor protein 53 (TP53) gene, as well as mutations in the breast cancer genes BRCA1/2. Molecular markers like BRCA1/2 mutations and homologous repair deficiency in HGSOC have been validated as predictive of response to platinum therapy and poly-ADP polymerase (PARP) inhibitors. Furthermore, recent research has shed light on the prognostic potential of immune cell populations infiltrating ovarian tumor tissue. The Cancer Genome Atlas (TCGA) and other genomic studies of HGSOC have conducted extensive genomic and transcriptomic analyses of HGSOC to delineate its genomic landscape and facilitate the development of targeted therapies for this highly lethal malignancy. Key findings from previous studies include the prevalent mutation of TP53 genes, frequent and widespread DNA copy number alterations, identification of transcriptional signatures associated with clinical outcome and molecular subtype, and diverse mechanisms of BRCA1/2 inactivation. However, most studies have focused on HGSOC of white populations, and there is limited comprehensive molecular characterization of East Asian HGSOC, including those from Korea. In this study, we aimed to discern clinical and molecular factors distinguishing 123 HGSOC patients from the Korean population through an integrated analysis of clinical features, germline variants, somatic genomic alterations, and the tumor immune microenvironment.
2024-06-01 | GSE268514 | GEO
Project description:High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers for women, with a low survival rate, no early markers, a high rate of recurrence, and few therapeutic options. Forskolin, an activator of cyclic AMP signaling, has several anticancer activities, including against HGSOC, but has limited use in vivo. Its water-soluble derivative, colforsin daropate, has the same mechanism of action as forskolin and is used to treat acute heart failure. Here, we investigated the potential of colforsin daropate as a treatment for HGSOC. We found that colforsin daropate induced cell cycle arrest and apoptosis in cultured HGSOC cells and spheroids, but not in normal fallopian tube secretory cells and ovarian surface epithelial cells. Colforsin daropate also prevented HGSOC cells from invading ovarian surface cell layers in culture. In vivo, colforsin daropate reduced tumor growth, synergized with cisplatin (a standard chemotherapy in ovarian cancer care), and improved host survival in a subcutaneous xenograft model. These anti-tumor effects of colforsin daropate were mediated in part by its reduction in the abundance and transcriptional activity of the oncoprotein c-MYC, which is often increased in HGSOC. Our findings demonstrate that colforsin daropate may be a promising therapeutic that could be combined with conventional therapies to treat HGSOC.
2024-11-19 | GSE280516 | GEO
Project description:As the most fatal type of gynecological cancers, high-grade serous ovarian cancer (HGSOC) exhibits heterogeneity that obstacles therapeutics. Up to date, the pathogenesis of HGSOC remains poorly understood. Here, we performed the deep single-cell RNA sequencing (scRNA-seq) using 59,324 cells isolated from seven treatment-naïve HGSOC patients at early or late tumor stages and five age-matched non-malignant ovarian samples. Our sequencing data showed a highly complex ecosystem of tumor, immune and stromal cells based on their marker genes and functional properties. We showed that normal ovary-specific fibroblasts were carried with the properties of mesenchymal stem cells (MSCs), which could be reprogrammed to cancer-associated fibroblasts. During tumor progression, matrix CAFs (mCAFs) could induce the EMT properties of the tumor cells. Furthermore, the analysis of the early stage tumors illuminated enrichments of IDO-expressing macrophages, CD8+ TRM cells, and the activated CD8+ TEX cells (TRM-CXCL13), whereas those tumors at the late stages loss these features and expressed signatures related to epithelial-to-mesenchymal transition (EMT) program. Also, we characterized a specific chemokine-receptor communication in HGSOC tumor microenvironment, which may contribute to shape the HGSOC features. Our compendia of scRNA-seq results provide valuable insights for understanding the landscape of HGSOC ecosystem, which will be helpful in advancing HGSOC cancer diagnosis and therapy and enabling personalized approaches to the treatment.
2022-06-10 | GSE184880 | GEO