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). 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.