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Significance Developmental signaling pathways play important roles in cancer initiation and therapeutic resistance. Poorly differentiated hepatocellular carcinomas (HCCs) usually show phenotypic resemblance to their ancestral precursor cells and are associated with poor clinical outcome. In a recent study, a dynamic oncofetal-like gene expression signature during liver development was identified from an in vitro hepatocyte differentiation model. Two subtypes of liver cancer with different oncofetal properties and upstream oncogenic drivers were found in clinical patients with poor prognosis. Clinically available small-molecule inhibitors HLM6474 and SIS3 specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and significantly inhibited tumorigenicity. Further treatment of HCC patients with specified small-molecular inhibitors according to subtype-specific biomarkers might accurately block the tumor-initiating steps and eliminate tumor progression.

A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets