Malignant Hepatoblast‐Like Cells Sustain Stemness via IGF2‐Dependent Cholesterol Accumulation in Hepatoblastoma

Abstract Hepatoblastoma, the most aggressive childhood liver tumor, poses significant challenges due to limited knowledge of its pathogenesis, particularly in poorly differentiated advanced tumors where the prognosis is dismal. Single‐cell sequencing provides an in‐depth exploration at the single‐cell level and offers a deep understanding of tumor heterogeneity. Herein, single‐cell transcriptomics analysis is used to identify a unique malignant‐hepatoblast (HB)‐like cell subpopulation as the possible origin of poorly differentiated hepatoblastoma. These cells are associated with an unfavorable clinical prognosis in hepatoblastoma patients. The malignant‐HB‐like cell subpopulation generated insulin‐like growth factor 2 (IGF2) to sustain stem‐like features by promoting abnormal cholesterol accumulation via SREBF2. IGF2 also stimulated fibroblast 2 to secrete collagen 1, intensifying tumor malignancy via the collagen 1/integrin α1 signaling pathway. This suggests that targeting malignant HB‐like cells by inhibiting IGF2‐induced pathways can lead to promising treatments for hepatoblastoma. Additionally, serum IGF2 levels may serve as a diagnostic biomarker for advanced hepatoblastoma. In summary, these findings provide valuable insight into the genesis and malignancy of hepatoblastoma and a foundation for more effective diagnostic tools and therapeutic strategies for this challenging disease.