Background & Aims: The primary cilium, an organelle that protrudes from cell surfaces, is essential for sensing extracellular signals. With disturbed cellular communication and chronic liver pathologies, this organelle’s dysfunctions have been linked to disorders, including polycystic liver disease (PLD) and Cholangiocarcinoma (CCA). The goal of this study was to elucidate the relationship between primary cilia and the crucial regulator of cellular proliferation, the epidermal growth factor receptor (EGFR) signaling pathway, which has been associated with various clinical conditions. Approach & Results: The study identified aberrant EGFR signaling pathways in cholangiocytes lacking functional primary cilia. Using liver-specific IFT88 knockout mice, a Pkhd1 mutant rat model, and human cell lines that didn’t have functional cilia. Cilia-deficient cholangiocytes showed persistent EGFR activation because of impaired receptor degradation, in contrast to their normal counterparts, where EGFR localization to the cilia promotes appropriate signaling. Using HDAC6 inhibitors to restore primary cilia accelerates EGFR degradation, thereby reducing maladaptive signaling. Importantly, experimental intervention with the HDAC6 inhibitor tubastatin A in an orthotopic rat model moved EGFR to cilia and reduced ERK phosphorylation. Concurrent administration of EGFR and HDAC6 inhibitors in cholangiocarcinoma and polycystic liver disease cells demonstrated synergistic anti-proliferative effects, which were associated with the restoration of functioning primary cilia. Conclusion: This study’s findings shed light on ciliary function and robust EGFR signaling with slower receptor turnover. We could use therapies that restore the function of primary cilia to treat EGFR-driven diseases in PLD and CCA.

中文翻译：

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胆管细胞纤毛缺陷诱导持续的表皮生长因子受体信号传导


背景和目标：初级纤毛，一种从细胞表面突出的细胞器，对于感知细胞外信号至关重要。由于细胞通讯紊乱和慢性肝脏病变，这种细胞器功能障碍与多囊肝病 （PLD） 和胆管癌 （CCA） 等疾病有关。本研究的目的是阐明初级纤毛与细胞增殖的关键调节因子表皮生长因子受体 （EGFR） 信号通路之间的关系，该通路与各种临床状况相关。方法和结果：该研究在缺乏功能性初级纤毛的胆管细胞中发现了异常的EGFR信号通路。使用肝脏特异性 IFT88 敲除小鼠、Pkhd1 突变大鼠模型和没有功能性纤毛的人类细胞系。纤毛缺陷型胆管细胞由于受体降解受损而表现出持续的 EGFR 激活，而正常胆管细胞则相反，EGFR 定位于纤毛促进适当的信号传导。使用 HDAC6 抑制剂恢复初级纤毛可加速 EGFR 降解，从而减少适应不良信号传导。重要的是，在原位大鼠模型中使用 HDAC6 抑制剂图巴他汀 A 进行实验干预可使 EGFR 移至纤毛并减少 ERK 磷酸化。在胆管癌和多囊肝病细胞中同时施用 EGFR 和 HDAC6 抑制剂显示出协同抗增殖作用，这与原代纤毛功能的恢复有关。结论： 本研究的结果揭示了纤毛功能和强大的 EGFR 信号传导，受体转换较慢。 我们可以使用恢复原代纤毛功能的疗法来治疗 PLD 和 CCA 中 EGFR 驱动的疾病。