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.

中文翻译：

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靶向 SHCBP1 通过恢复导管癌纤毛发生来抑制肿瘤进展


初级纤毛检测环境信号并将其传输到细胞中。以独特的生物活性为特征的导管癌子集中不存在原发纤毛，恢复具有正常功能的纤毛已被证明对某些癌症类型具有治疗潜力。因此，阐明导管癌纤毛缺失的潜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 和纤毛之间的联系。转基因小鼠中的 Shcbp1 敲除极大地阻止了肿瘤的进展和转移，延长了生存期。单细胞转录组分析揭示了 SHCBP1 缺陷与肿瘤纤毛生成增加之间的功能联系。 SHCBP1 消融通过增强 Rab8 GTPase 活性和 Rab8GTP 在 MBR 内的定位，促进中体残余 (MBR) 和中心体之间的接近，从而恢复了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发生的恢复。对大量导管癌患者的分析表明，SHCBP1 诱导的纤毛缺失与患者预后之间存在负相关。通过 SHCBP1 消融恢复纤毛发生在患者来源的异种移植模型中产生了治疗效果。总之，这项研究表明，通过 SHCBP1 缺陷诱导 MBR-中心体接近可重新激活纤毛发生，为治疗无纤毛导管癌提供独特的机会。