Cholangiocyte Ciliary Defects Induce Sustained Epidermal Growth Factor Receptor Signaling

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). This study aimed to clarify the interaction between primary cilia and the critical regulator of cellular proliferation known as the epidermal growth factor receptor (EGFR) signaling pathway, which has been linked to several clinical conditions. Approach & Results: The study identified abnormal EGFR signaling pathways inside cholangiocytes lacking functioning primary cilia using liver-specific IFT88 knockout mice, a Pkhd1 mutant rat model, and human cell lines with ciliary deficiencies. Cilia-deficient cholangiocytes showed persistent EGFR activation because of impaired receptor degradation, in contrast to their normal counterparts where EGFR localization to cilia promotes appropriate signaling. By using HDAC6 inhibitors to restore primary cilia, EGFR degradation was accelerated, which in turn reduced the maladaptive signaling. Importantly, EGFR was moved to cilia because of experimental intervention with the HDAC6 inhibitor tubastatin A in an orthotopic rat model, along with a reduction in the phosphorylation of ERK. In cholangiocarcinoma and polycystic liver disease cells, concurrent administration of EGFR and HDAC6 inhibitors displayed synergistic anti-proliferative effects that were related to the restoration of functioning primary cilia. Conclusion: The findings of this study shed light on defective ciliary function and robust EGFR signaling with slower receptor turnover. A potential method for treating EGFR-driven pathologies in PLD and CCA is the pharmacological restoration of primary cilia function.