Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.

中文翻译：

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NOTCH 和 SOX2 的相互抑制塑造了三阴性乳腺癌的肿瘤细胞可塑性和治疗逃逸。


癌细胞可塑性是导致三阴性乳腺癌 （TNBC） 化疗和靶向治疗失败的重要原因。治疗诱导的肿瘤细胞可塑性和相关耐药性的分子机制在很大程度上是未知的。使用全基因组 CRISPR-Cas9 筛选，我们研究了用 γ 分泌酶抑制剂 （GSI） 处理的 NOTCH 驱动的 TNBC 的逃逸机制，并确定 SOX2 是对 Notch 抑制的耐药靶点。我们描述了 Notch 信号传导和 SOX2 之间的一种新的相互抑制反馈机制。具体来说，Notch 信号转导通过其 HEY 家族的靶基因抑制 SOX2 表达，SOX2 通过与 RBPJ 的直接相互作用抑制 Notch 信号转导。这种机制塑造了不同的细胞状态，NOTCH 阳性 TNBC 更像上皮细胞，而 SOX2 表达与上皮-间充质转化相关，诱导癌症干细胞特征和 GSI 耐药。为了抵消单药治疗诱导的肿瘤复发，我们分别在 NOTCH 抑制剂敏感和耐药的 TNBC 异种移植中评估了 GSI-紫杉醇和达沙替尼-紫杉醇联合治疗。这些不同的预防组合和二线治疗选择依赖于 TNBC 中 NOTCH1 和 SOX2 的表达，能够诱导肿瘤生长控制并减轻转移负荷。