基于 DNA 超分子水凝胶的保护性 NK 细胞储库用于增强三阴性乳腺癌治疗
Protective NK Cell Reservoir Based on DNA Supramolecular Hydrogel for Enhanced Triple-Negative Breast Cancer Therapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
准间充质干细胞样细胞中的 EMT-纤毛信号驱动治疗耐药，是三阴性乳腺癌的可成药脆弱点
英文原题：EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer.
查看英文原题
EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer.
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中文摘要
癌症治疗耐药部分由肿瘤细胞表型异质性和可塑性介导，后者由上皮-间质转化（EMT）促成。然而，EMT 在人类癌症治疗应答中的作用尚未充分理解。研究者从人三阴性乳腺癌（TNBC）构建患者来源类器官（PDO），并研究其化疗应答。化疗可杀死 PDO 中大多数肿瘤细胞，但部分恶性细胞选择性存活；这些细胞已激活 EMT 程序、进入准间质干细胞样状态并出现初级纤毛。研究者开发了一系列小分子纤毛发生抑制剂，并显示使用这些抑制剂或通过基因方式清除初级纤毛，均足以通过 NF-κB 诱导的细胞死亡抑制化疗耐药。研究结论认为，EMT-纤毛信号轴可在具有纤毛的准间质干细胞样细胞中诱导化疗耐药，帮助肿瘤逃避化疗，并构成人类 TNBC 中可药物靶向的弱点。
展开英文摘要原文
Cancer therapeutic resistance is mediated, in part, by phenotypic heterogeneity and the plasticity of tumor cells, the latter being enabled by epithelial-mesenchymal transition (EMT).
However, EMT in human cancer therapeutic response remains poorly understood.
We developed patient-derived organoids (PDOs) from human triple-negative breast cancer (TNBC) and investigated their response to chemotherapy.
We found that chemotherapy treatment kills the bulk of tumor cells in PDOs, but there is selective survival of malignant cells that had activated an EMT program, entered a quasi-mesenchymal, stem cell-like state and display primary cilia.
We developed a family of small-molecule inhibitors of ciliogenesis and show that treatment with these inhibitors, or genetic ablation of primary cilia, is sufficient to suppress this chemoresistance via NF B-induced cell death.
We conclude that an EMT-ciliary signaling axis induces chemoresistance in quasi-mesenchymal ciliated stem-like cells to help tumors evade chemotherapy and represents a druggable vulnerability in human TNBC.
论文信息
- 作者
- Tessier CE、Derrien J、Dupuy AMM、Pelé T、Moquet M、Roul J、Douillard E、El Harrif C
- 第一作者单位
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Équipe Labellisée LIGUE Contre le Cancer, Nantes, F-44000, France.France
- 通讯作者单位
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Équipe Labellisée LIGUE Contre le Cancer, Nantes, F-44000, France. vincent.guen@inserm.fr.France
- 期刊
- EMBO molecular medicine2025 Oct
- 原文标识
- PubMed 40859055 · DOI 10.1038/s44321-025-00289-1
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