基于类器官的单细胞测序揭示了多西紫杉醇治疗胃癌过程中的谱系进化。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-03-19 DOI:10.1016/j.canlet.2025.217617

Dejun Yang , Xin Zhang , Zunqi Hu , Qiang Sun , Hongbing Fu , Jun Yao , Binbin Zheng , Xin Zhang , Weijun Wang

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引用次数: 0

摘要

胃癌多西紫杉醇耐药是一个重大的治疗挑战。在这项研究中，我们建立了对多西他赛敏感和耐药的胃癌类器官，并进行了单细胞RNA测序以鉴定细胞和分子的改变。我们观察到细胞群的显著变化，耐药组的分泌性、免疫趋化性和移行性胃癌细胞增加。关键耐药相关基因，包括FOS、IFI27和PTTG1IP，在耐药类器官和胃癌患者中上调。伪时间轨迹分析显示，抗性细胞主要占据末段分化阶段。抑制FOS、IFI27和PTTG1IP增强细胞系和类器官对多西他赛的敏感性，调节ROS的产生、自噬和凋亡。在体内，沉默这些基因减少了肿瘤生长，以响应多西紫杉醇。这些发现提示，靶向FOS、IFI27和PTTG1IP可以克服耐药，改善胃癌患者的治疗效果。

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Organoid-based single cell sequencing revealed the lineage evolution during docetaxel treatment in gastric cancer

Docetaxel resistance in gastric cancer poses a major therapeutic challenge. In this study, we established docetaxel-sensitive and -resistant gastric cancer organoids and performed single-cell RNA sequencing to identify cellular and molecular alterations. We observed significant shifts in cell populations, with increased secretory, immune-chemotactic, and transitional gastric cancer cells in the resistant group. Key resistance-related genes, including FOS, IFI27, and PTTG1IP, were upregulated in resistant organoids and gastric cancer patients. A pseudo-time trajectory analysis revealed that resistant cells predominantly occupied terminal differentiation stages. Knocking down FOS, IFI27, and PTTG1IP enhanced docetaxel sensitivity in both cell lines and organoids, regulating ROS production, autophagy, and apoptosis. In vivo, silencing these genes reduced tumor growth in response to docetaxel. These findings suggest that targeting FOS, IFI27, and PTTG1IP could overcome resistance and improve treatment outcomes for gastric cancer patients.

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.