Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids
Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic 'fetal' and WNT-high 'embryonal', displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes. Gene regulatory network analysis reveals enrichment of regulons related to hepatic functions such as bile acid, lipid and xenobiotic metabolism in the fetal subtype but not in the embryonal subtype. In addition, the dichotomous expression pattern of the transcription factors HNF4A and LEF1 allows for a clear distinction between the fetal and embryonal tumor cells. We also perform high-throughput drug screening using patient-derived tumor organoids and identify sensitivity to HDAC inhibitors. Intriguingly, embryonal and fetal tumor organoids are sensitive to FGFR and EGFR inhibitors, respectively, indicating a dependency on EGF/FGF signaling in hepatoblastoma tumorigenesis. In summary, our data uncover the molecular and drug sensitivity landscapes of hepatoblastoma and pave the way for the development of targeted therapies.
Authors
- Lianne J. Kraaier (ORCID: https://orcid.org/0000-0003-2796-3512)
- Marius C. van den Heuvel (ORCID: https://orcid.org/0000-0001-6985-7107)
- Thomas A. Kluiver (ORCID: https://orcid.org/0000-0003-2224-480X)
- Marc van de Wetering (ORCID: https://orcid.org/0000-0002-8195-9939)
- Vicky Amo-Addae
- Femke Ringnalda (ORCID: https://orcid.org/0000-0002-0684-4613)
- Thanasis Margaritis (ORCID: https://orcid.org/0000-0003-4040-2015)
- Wout Megchelenbrink (ORCID: https://orcid.org/0000-0002-2895-3511)
- Kornelius Kerl (ORCID: https://orcid.org/0000-0002-5676-8102)
- Jeff DeMartino (ORCID: https://orcid.org/0000-0001-7366-4789)
- Hendrik G. Stunnenberg (ORCID: https://orcid.org/0000-0002-0066-1576)
- Vincent Erwin de Meijer (ORCID: https://orcid.org/0000-0002-7900-5917)
- Evelien W. Duiker (ORCID: https://orcid.org/0000-0002-9450-5282)
- Selma Eising
- Flavia W. de Faria (ORCID: https://orcid.org/0000-0003-0162-6331)
- Ronald R. de Krijger (ORCID: https://orcid.org/0000-0001-6871-1296)
- Hans Clevers (ORCID: https://orcid.org/0000-0002-3077-5582)
- Philip Lijnzaad (ORCID: https://orcid.org/0000-0002-7535-583X)
- Jan J. Molenaar (ORCID: https://orcid.org/0000-0002-2007-0431)
- Weng Chuan Peng (ORCID: https://orcid.org/0000-0001-5467-5458)
- József Zsíros
- Ruben H J de Kleine (ORCID: https://orcid.org/0000-0003-3975-3184)
- Daniel Münter (ORCID: https://orcid.org/0000-0001-8823-0238)
- Yuyan Lu (ORCID: https://orcid.org/0009-0000-6374-1357)
- Stephanie A Schubert (ORCID: https://orcid.org/0000-0002-8655-1350)
Institutions
- Roche (Switzerland) (CH)
- Royal Netherlands Academy of Arts and Sciences (NL)
- University Medical Center Groningen (NL)
- University of Groningen (NL)
- Beijing University of Chinese Medicine (CN)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University Medical Center Utrecht (NL)
- University Hospital Münster (DE)
- Oncode Institute (NL)
- University of Campania "Luigi Vanvitelli" (IT)
- Princess Máxima Center (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1038/s41467-024-52757-w
- Citations
- 22
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 6.27
Funders
- Stichting Kinderen Kankervrij