Single cell profiling of female breast fibroadenoma reveals distinct epithelial cell compositions and therapeutic targets.
Single cell profiling of female breast fibroadenoma reveals distinct epithelial cell compositions and therapeutic targets.
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DOI：
10.1038/s41467-023-39059-3
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发表时间：
2023-06-16
影响因子：
16.6
通讯作者：
Huang, Jian
中科院分区：
文献类型：
--
作者：
Chen, Zhigang;Zhang, Yi;Li, Wenlu;Gao, Chenyi;Huang, Fengbo;Cheng, Lu;Jin, Menglei;Xu, Xiaoming;Huang, Jian
纤维腺瘤（FA）是女性最常见的乳腺肿瘤。由于其机制尚不清楚，缺乏可重复的人体模型，目前还没有药物被批准用于FA干预。在这里，使用人类脂肪酸和正常乳腺组织的单细胞RNA测序，我们观察不同的细胞组成和上皮结构的变化脂肪酸。有趣的是，上皮细胞表现出雌激素敏感性和雌激素抗性机制（ERBB 2，BCL 2和CCND 1途径）的雌激素响应功能签名和同步激活。我们开发了一种人类可扩展的FA类器官系统，并观察到大多数类器官似乎对他莫昔芬具有耐药性。他莫昔芬与ERBB 2、BCL 2或CCND 1抑制剂的个体化组合可以显著抑制他莫昔芬耐药类器官的活力。因此，我们的研究提出了一个概述人类FA在单细胞分辨率，概述了FA和正常乳腺上皮之间的结构和功能差异，特别是，提供了一个潜在的治疗策略乳腺脂肪酸。纤维腺瘤的发生与乳腺癌的长期风险增加有关，然而，缺乏模型使得对这一机制的理解不清楚。在这里，作者使用单细胞RNA-seq来识别上皮细胞的失调，并开发类器官模型来研究治疗抗性。
Fibroadenomas (FAs) are the most common breast tumors in women. No pharmacological agents are currently approved for FA intervention owing to its unclear mechanisms and a shortage of reproducible human models. Here, using single-cell RNA sequencing of human FAs and normal breast tissues, we observe distinct cellular composition and epithelial structural changes in FAs. Interestingly, epithelial cells exhibit hormone-responsive functional signatures and synchronous activation of estrogen-sensitive and hormone-resistant mechanisms (ERBB2, BCL2 and CCND1 pathways). We develop a human expandable FA organoid system and observe that most organoids seem to be resistant to tamoxifen. Individualized combinations of tamoxifen with ERBB2, BCL2 or CCND1 inhibitors could significantly suppress the viability of tamoxifen-resistant organoids. Thus, our study presents an overview of human FA at single-cell resolution that outlines the structural and functional differences between FA and normal breast epithelium and, in particular, provides a potential therapeutic strategy for breast FAs. Fibroadenoma occurrence is linked to increased long-term risk of breast carcinoma, however, the lack of models has made understanding this mechanism unclear. Here, the authors use single cell RNA-seq to identify dysregulation of epithelial cells and develop organoid models to study treatment resistance.
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影响因子：
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作者：
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