SALL4 Is Required for YAP1-Dependent Malignant and Regenerative Hepatocyte-to-Cholangiocyte Reprogramming

Area of Science:

• Hepatobiliary biology
• Molecular mechanisms of liver disease
• Cancer biology

Background:

• Hepatocytes (HC) can reprogram into cholangiocytes (CC) for liver repair but also undergo malignant transformation into cholangiocarcinoma (CCA).
• The molecular drivers of hepatocyte plasticity in liver disease remain incompletely understood.
• Spalt-like transcription factor 4 (SALL4) is an oncofetal transcription factor implicated in cell fate transitions.

Purpose of the Study:

• To investigate the role of SALL4 in hepatocyte (HC) reprogramming towards the biliary lineage in both malignant and regenerative contexts.
• To elucidate the molecular mechanisms underlying SALL4-mediated HC plasticity.
• To assess the therapeutic potential of targeting SALL4 in liver cancer.

Main Methods:

• Utilized Sleeping Beauty hydrodynamic tail vein injection to create murine liver cancer models for studying HC-to-CCA transformation.
• Employed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced cholestasis model to investigate regenerative HC-to-CC reprogramming.
• Analyzed the impact of SALL4 manipulation (loss and overexpression) on HC fate transitions and downstream effectors like Bmi1.

Main Results:

• SALL4 is essential for myristoylated Akt-YAP1S127A-driven HC-to-CCA transformation, with SALL4 loss suppressing malignant reprogramming.
• Sall4 overexpression prevented YAP1S127A-driven CCA but promoted expansion of liver progenitor cell (LPC)-like fatty HCs.
• In cholestasis models, SALL4 deletion enhanced HC-to-LPC activation but impaired LPC differentiation into mature CCs.
• Proposed Bmi1 as a key downstream effector of SALL4 in YAP1-dependent HC-to-CCA transformation.

Conclusions:

• SALL4 acts as a critical regulator of hepatocyte plasticity in both malignant transformation and regenerative processes.
• The YAP1-SALL4-BMI1 axis is identified as a key pathway in HC-to-CCA reprogramming.
• SALL4 represents a potential therapeutic target for specific subtypes of cholangiocarcinoma.