Targeting SHCBP1 Inhibits Tumor Progression by Restoring Ciliogenesis in Ductal Carcinoma.

IF 12.5 1区 医学 Q1 ONCOLOGY
Wengui Shi, Lianshun Li, Huiming Zhao, Zhengyang Li, Zhijian Ma, Qianlin Gu, Huili Ye, Xiangyan Jiang, Yuman Dong, Long Qin, Huinian Zhou, Zeyuan Yu, Zuoyi Jiao
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引用次数: 0

Abstract

Primary cilia detect and transmit environmental signals into cells. Primary cilia are absent in a subset of ductal carcinomas characterized by distinctive biological activities, and recovery of cilia with normal functionality has been shown to have therapeutic potential in some cancer types. Therefore, elucidation of the underlying mechanism and clinical significance of ciliary loss in ductal carcinomas could help develop effective treatment strategies. Here, we identified a link between SHCBP1 and cilia in ductal carcinomas. Shcbp1 knockout in transgenic mice profoundly impeded tumor progression and metastasis, prolonging survival. Single-cell transcriptome analysis revealed a functional connection between SHCBP1 deficiency and increased tumor ciliogenesis. SHCBP1 ablation restored ciliogenesis in unciliated ductal carcinoma by promoting the proximity between the midbody remnant (MBR) and centrosome through enhanced Rab8 GTPase activity and Rab8GTP positioning within the MBR. Inhibition of tumor progression by SHCBP1 loss relied on the recovery of ciliogenesis. Analysis of a large cohort of patients with ductal carcinoma revealed a negative correlation between SHCBP1-induced ciliary loss and patient prognosis. Restoring ciliogenesis via SHCBP1 ablation elicited therapeutic effects in patient-derived xenograft models. Together, this study delineates that induction of MBR-centrosome proximity through SHCBP1-deficiency reactivates ciliogenesis, offering unique opportunities for the treatment of unciliated ductal carcinomas.

靶向 SHCBP1 可通过恢复乳腺导管癌中的纤毛生成抑制肿瘤进展
原生纤毛能探测环境信号并将其传递到细胞中。原发性纤毛缺失存在于一部分具有独特生物活性的导管癌中,而恢复纤毛的正常功能已被证明在某些癌症类型中具有治疗潜力。因此,阐明导管癌中纤毛缺失的内在机制和临床意义有助于制定有效的治疗策略。在这里,我们发现了导管癌中SHCBP1与纤毛之间的联系。在转基因小鼠中敲除 Shcbp1 能显著抑制肿瘤的发展和转移,延长生存期。单细胞转录组分析揭示了 SHCBP1 缺乏与肿瘤纤毛生成增加之间的功能性联系。SHCBP1 消融通过增强 Rab8 GTPase 活性和 Rab8GTP 在中体残基(MBR)内的定位,促进中体残基与中心体之间的接近,从而恢复无纤毛导管癌的纤毛生成。SHCBP1 缺失对肿瘤进展的抑制依赖于纤毛生成的恢复。对一大批导管癌患者的分析表明,SHCBP1 诱导的纤毛缺失与患者的预后呈负相关。通过消融 SHCBP1 恢复纤毛生成在患者异种移植模型中产生了治疗效果。总之,这项研究阐明了通过 SHCBP1 缺失诱导 MBR-中心体接近可重新激活纤毛生成,为治疗无纤毛导管癌提供了独特的机会。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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