CSRP1 in stromal fibroblasts drives high-grade serous ovarian cancer development [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE278927 | GEO | 2024/10/23
REPOSITORIES: GEO
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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.
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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.
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Project description:CSRP1 in stromal fibroblasts drives high-grade serous ovarian cancer development [ChIP-seq]
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