A single-cell landscape of high-grade serous ovarian cancer

Abstract

Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis 1 . To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA-seq (scRNA-seq) to profile ~11,000 cells from 22 ascites specimens from 11 HGSOC patients. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We find that the previously described "immunoreactive" and "mesenchymal" subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells 2 . Malignant cell variability was partly explained by heterogeneous copy number alterations (CNA) patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in scRNA-seq of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient-ascites-derived xenograft models. Inhibition of the JAK/STAT-pathway, which was expressed in both malignant cells and CAFs, had potent anti-tumor activity in primary short-term cultures and PDX models. Our work contributes to resolving the HSGOC landscape 3-5 and provides a resource for the development of novel therapeutic approaches.

Single-Cell Analysis of Different Stages of Oral Cancer Carcinogenesis in a Mouse Model

“…Single-cell technology can also be used to elucidate the mechanisms of cell resistance and genomic and transcription dysregulation [21]. In ovarian cancer, malignant cells and cancer-related fibroblasts express genes related to the JAK-STAT signaling pathway, and inhibiting this pathway was reported to promote effective anti-tumor ability in the primary cell cultures and xenograft models of patients [22]. Tumor-infiltrating lymphocytes are a potential benefit of immunotherapy and enhance clinical response to cancer, and analysis of the T-cell population in hepatoma tissues revealed that the LAYN gene in infiltrating T cells can inhibit the function of regulatory T cells and CD8 T cells [10].…”

High-throughput approaches for precision medicine in high-grade serous ovarian cancer

“…Additionally, in a disease characterized by extensive intraperitoneal dissemination, multiregion molecular profiling of primary tumors and metastases can be of value for discerning the biology underlying HGSC progression [ 32 – 34 ]. Despite the loss of spatial microenvironment context, single-cell technologies can also provide insights into intratumor heterogeneity [ 35 , 36 ]. Further large-scale studies using these emerging approaches may shed light into how intratumor heterogeneity manifests in clinical outcomes such as therapeutic resistance.…”

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

“…Single-cell transcriptomics has also been applied to high-grade serous ovarian cancer primary tumors and patient-derived xenograft models. Different cell types were identified in the tumors, including epithelial cells, cancer associated fibroblasts, macrophages, dendritic, B and T cells [ 177 ]. In addition, inter-patient heterogeneity was found in cancer cells (different subpopulations), but not in macrophages and fibroblasts.…”