Single-cell RNA-sequencing reveals transcriptional dynamics of estrogen-induced dysplasia in the ovarian surface epithelium

Abstract

Estrogen therapy increases the risk of ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. Both in vivo and in vitro, ovarian surface epithelial (OSE) cells exposed to estradiol develop a subpopulation that loses cell polarity, contact inhibition, and forms multi-layered foci of dysplastic cells with increased susceptibility to transformation. Here, we use single-cell RNA-sequencing to characterize this dysplastic subpopulation and identify the transcriptional dynamics involved in its emergence. Estradiol-treated cells were characterized by up-regulation of genes associated with proliferation, metabolism, and survival pathways. Pseudotemporal ordering revealed that OSE cells occupy a largely linear phenotypic spectrum that, in estradiol-treated cells, diverges towards cell state consistent with the dysplastic population. This divergence is characterized by the activation of various cancer-associated pathways including an increase in Greb1 which was validated in fallopian tube epithelium and human ovarian cancers. Taken together, this work reveals possible mechanisms by which estradiol increases epithelial cell susceptibility to tumour initiation.

Single-cell RNA sequencing in cancer: Applications, advances, and emerging challenges

“…The genetic profile of the respective CAF subtype is associated with a unique functional program and has an independent prognostic capability in the clinical cohort through its association with metastatic disease. 112 Lin et al 113 used scRNA-seq for profiling single-cell transcriptomes according to dissociated primary tumors or metastasis-related biopsies of patients with pancreatic ductal adenocarcinoma (PDAC) and revealed distinct cell types in primary and metastatic PDAC tissues, including tumor cells, endothelial cells, CAFs, and immune cells.…”

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

“…In addition, inter-patient heterogeneity was found in cancer cells (different subpopulations), but not in macrophages and fibroblasts. Single-cell RNA-seq information has also been used to detect chromosomal copy number alterations in malignant epithelial cancer cells [ 177 ], single nucleotide variants among cancer cells and can predict chemoresistance or estradiol responsiveness [ 172 , 173 ]. In contrast, testicular cancer single-cell transcriptomics is yet to be studied in detail.…”

Nursing Genetic Research: New Insights Linking Breast Cancer Genetics and Bone Density

“…17-β estradiol promotes ovarian tumor growth in mouse models with GREB1 a key mediator of this process, so the mechanism involved probably implies the upregulation of collagen I expression [ 24 ]. Recently, it has also been proposed that GREB1 expression is highest in murine dysplastic ovarian surface epithelial and fallopian tube epithelium, suggesting that GREB1 may play a role in the initiation of tumor formation in both cell types [ 25 ]. Overall, the reported results indicate a major function for GREB1 in estrogen-dependent conditions in epithelial ovarian cancers [ 17 ].…”