EHF/ESE3 loss causes prostate epithelial cell plasticity and cancer (Murine models - single cell RNA-seq data)

Phenotypic plasticity associated with epithelial to mesenchymal transition occurs in late stage of several type of cancers and results in metastatic spread and enhanced resistance to therapy. Understanding these events is important to prevent and cure this aberrant conversion. Intriguingly, primary prostate tumors are by definition androgen-sensitive and display a strong luminal identity. In contrast, castration resistant prostate tumors are characterized by change of identity, insensitivity to androgen ablation therapy. Thus, an active mechanism maintain the normal physiologic androgen responsive status preventing plasticity. In this study, we show for the first time that conditional knockout of the epithelial specific ETS factor EHF/ESE3, which is a top ranking expressed TF in the normal prostate, is sufficient to determine a dramatic loss of cell identity and transformation. Bulk and single-cell RNA sequencing revealed that loss of EHF/ESE3 reactivate an aberrant ambiguous cell program with acquisition of endothelial and stromal features. Astonishingly, crossing the cEHF-KO mice with TMPRSS2-ERG mice, resulted in complete conversion of the epithelial component to a stromal like status supported by tracing the epithelial cells TMPRSS2ERG/eGFP positive. Notably, integration of data from prostate cancer patients datasets support that cEHF-KO and cEHF-KO/R26ERG recapitulate stem cell like and neuroendocrine prostate tumors and that are enriched of cancer stem cell-like cells.

与上皮间质转化（epithelial to mesenchymal transition）相关的表型可塑性，可发生于多种癌症的晚期阶段，最终导致肿瘤转移播散及治疗抗性增强。阐明此类事件的分子机制，对预防并纠正这种异常细胞转化具有重要意义。有趣的是，原发性前列腺肿瘤本质上为雄激素敏感（androgen-sensitive）肿瘤，且表现出强烈的管腔细胞特性；与之相反，去势抵抗性前列腺肿瘤以细胞特性改变、对雄激素剥夺治疗（androgen ablation therapy）不敏感为特征。由此可见，机体存在活跃的调控机制以维持正常的生理性雄激素应答状态，阻止细胞可塑性的异常激活。本研究首次证实，正常前列腺组织中高表达的上皮特异性ETS转录因子EHF/ESE3的条件性敲除（conditional knockout），足以引发细胞特性的显著丧失与恶性转化。通过批量及单细胞RNA测序（bulk and single-cell RNA sequencing）分析发现，EHF/ESE3的缺失会重新激活异常的模糊细胞程序，使细胞获得内皮与间质特征。令人惊讶的是，将cEHF条件性敲除小鼠与TMPRSS2-ERG小鼠进行杂交后，通过追踪TMPRSS2ERG/eGFP阳性的上皮细胞，证实上皮组分完全转化为间质样状态。值得注意的是，整合前列腺癌患者数据集的分析结果表明，cEHF敲除及cEHF敲除/R26ERG模型可重现干细胞样及神经内分泌前列腺癌（neuroendocrine prostate tumors）的特征，且此类模型中富集癌症干细胞样细胞（cancer stem cell-like cells）。