NOTCH和SOX2的相互抑制塑造了肿瘤细胞的可塑性和三阴性乳腺癌的治疗逃逸。

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-10-30 DOI:10.1038/s44321-024-00161-8
Morgane Fournier, Joaquim Javary, Vincent Roh, Nadine Fournier, Freddy Radtke
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引用次数: 0

摘要

癌细胞可塑性是三阴性乳腺癌(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及相关耐药性的分子机制在很大程度上尚属未知。通过全基因组 CRISPR-Cas9 筛选,我们研究了用γ-分泌酶抑制剂(GSI)治疗 NOTCH 驱动的 TNBC 的逃逸机制,并确定 SOX2 为 Notch 抑制的耐药靶点。我们描述了Notch信号传导与SOX2之间一种新型的相互抑制反馈机制。具体来说,Notch信号通过其HEY家族的靶基因抑制SOX2的表达,而SOX2则通过与RBPJ的直接相互作用抑制Notch信号。这种机制形成了不同的细胞状态,Notch 阳性的 TNBC 更像上皮细胞,而 SOX2 的表达则与上皮-间质转化相关,诱导癌症干细胞特征和 GSI 抗性。为了应对单药治疗诱导的肿瘤复发,我们分别在对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-紫杉醇联合疗法。这些不同的预防性组合和二线治疗方案依赖于 TNBC 中 NOTCH1 和 SOX2 的表达,能够诱导肿瘤生长控制并减少转移负荷。
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Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer.

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.

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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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