Liver cancer medical and engineering intersection - Distinct WNT signaling and drug sensitivity signatures in hepatoblastoma tumors and organoids

Hepatoblastoma is the most common pediatric liver cancer and almost always carries WNT-activating CTNNB1 mutations, but exhibits significant molecular heterogeneity. To characterize this heterogeneity and identify new targeted therapies, we performed comprehensive analyses of hepatoblastoma and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identified two distinct tumor epithelial signatures: liver "fetal" and WNT-high "embryo", which displayed distinct patterns of WNT signaling. The fetal group was enriched for liver-specific WNT targets, while the embryonic group was enriched for canonical WNT target genes. Gene regulatory network analysis revealed that regulators associated with liver functions such as bile acid, lipid, and xenobiotic metabolism were enriched in the fetal subtype, but not in the embryonic subtype. In addition, the dichotomous expression patterns of the transcription factors HNF4A and LEF1 allowed for clear distinction between fetal and embryonic tumor cells. We also used patient-derived tumor organoids for high-throughput drug screening and determined sensitivity to HDAC inhibitors. Interestingly, embryonic and fetal tumor organoids were sensitive to FGFR and EGFR inhibitors, respectively, suggesting that hepatoblastoma tumorigenesis is dependent on EGF/FGF signaling. In conclusion, our data reveal the molecular and drug sensitivity landscape of hepatoblastoma and pave the way for the development of targeted therapies.

Innovation: Multi-omics technology (single-cell RNA-seq/ATAC-seq, spatial transcriptomics) was used for the first time to comprehensively map the molecular heterogeneity of hepatoblastoma. Hepatoblastoma was innovatively divided into two subtypes with different transcriptional characteristics, "fetal" and "embryo". The binary expression patterns of HNF4A and LEF1 were revealed, which can accurately distinguish tumor cell subtypes. Targeted targeted therapeutic drugs were determined through systematic screening of patient-derived organoids. Research inspiration: Demonstrated the great value of multi-omics integrated analysis in tumor precision medicine. Revealed the key impact of tumor heterogeneity on targeted therapy. Provided a new personalized treatment strategy based on molecular characteristics. Proved the important role of tumor organoids in drug screening. Extension of ideas: Explore the application of similar multi-omics analysis methods in other pediatric tumors. Study the deep regulatory mechanism of the WNT signaling pathway in tumorigenesis. Develop precision treatment plans based on molecular subtypes. Explore the synergistic therapeutic potential of HDAC, FGFR and EGFR inhibitors. In-depth analysis of the abnormal expression mechanism of liver development-related genes in tumors. Design more accurate molecular typing and treatment strategies. Study the long-term value of tumor organoids in personalized medicine.