Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada.
PLoS Genet. 2018 Nov 12;14(11):e1007788. doi: 10.1371/journal.pgen.1007788. eCollection 2018 Nov.
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.
雌激素治疗会增加卵巢癌的风险，外源性雌二醇会加速小鼠模型中卵巢癌的发病。在体内和体外，暴露于雌二醇的卵巢表面上皮 (OSE) 细胞会发展出失去细胞极性、接触抑制的亚群，并形成具有更高转化易感性的异型细胞的多层焦点。在这里，我们使用单细胞 RNA 测序来描述这种异型细胞亚群，并确定其出现所涉及的转录动态。用雌二醇处理的细胞的特征是与增殖、代谢和存活途径相关的基因上调。假时间排序表明，OSE 细胞占据了一个主要的线性表型谱，在雌二醇处理的细胞中，该谱向与异型细胞群一致的细胞状态发散。这种发散的特征是各种与癌症相关的途径的激活，包括 Greb1 的增加，这在输卵管上皮和人类卵巢癌中得到了验证。总之，这项工作揭示了雌二醇增加上皮细胞对肿瘤起始易感性的可能机制。
