Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids
Abstract 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...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-52757-w |
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| author | Thomas A. Kluiver Yuyan Lu Stephanie A. Schubert Lianne J. Kraaier Femke Ringnalda Philip Lijnzaad Jeff DeMartino Wouter L. Megchelenbrink Vicky Amo-Addae Selma Eising Flavia W. de Faria Daniel Münter Marc van de Wetering Kornelius Kerl Evelien Duiker Marius C. van den Heuvel Vincent E. de Meijer Ruben H. de Kleine Jan J. Molenaar Thanasis Margaritis Hendrik G. Stunnenberg Ronald R. de Krijger József Zsiros Hans Clevers Weng Chuan Peng |
| author_facet | Thomas A. Kluiver Yuyan Lu Stephanie A. Schubert Lianne J. Kraaier Femke Ringnalda Philip Lijnzaad Jeff DeMartino Wouter L. Megchelenbrink Vicky Amo-Addae Selma Eising Flavia W. de Faria Daniel Münter Marc van de Wetering Kornelius Kerl Evelien Duiker Marius C. van den Heuvel Vincent E. de Meijer Ruben H. de Kleine Jan J. Molenaar Thanasis Margaritis Hendrik G. Stunnenberg Ronald R. de Krijger József Zsiros Hans Clevers Weng Chuan Peng |
| author_sort | Thomas A. Kluiver |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-e9c310a9ac5d476ba9c8f3c8d25d32c8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e9c310a9ac5d476ba9c8f3c8d25d32c82024-11-24T12:34:37ZengNature PortfolioNature Communications2041-17232024-11-0115111710.1038/s41467-024-52757-wDivergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoidsThomas A. Kluiver0Yuyan Lu1Stephanie A. Schubert2Lianne J. Kraaier3Femke Ringnalda4Philip Lijnzaad5Jeff DeMartino6Wouter L. Megchelenbrink7Vicky Amo-Addae8Selma Eising9Flavia W. de Faria10Daniel Münter11Marc van de Wetering12Kornelius Kerl13Evelien Duiker14Marius C. van den Heuvel15Vincent E. de Meijer16Ruben H. de Kleine17Jan J. Molenaar18Thanasis Margaritis19Hendrik G. Stunnenberg20Ronald R. de Krijger21József Zsiros22Hans Clevers23Weng Chuan Peng24Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Albert-Schweitzer-Campus 1Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Albert-Schweitzer-Campus 1Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Albert-Schweitzer-Campus 1Department of Pathology and Medical Biology, University Medical Center GroningenDepartment of Pathology and Medical Biology, University Medical Center GroningenDepartment of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center GroningenDepartment of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center GroningenPrincess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25Abstract 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.https://doi.org/10.1038/s41467-024-52757-w |
| spellingShingle | Thomas A. Kluiver Yuyan Lu Stephanie A. Schubert Lianne J. Kraaier Femke Ringnalda Philip Lijnzaad Jeff DeMartino Wouter L. Megchelenbrink Vicky Amo-Addae Selma Eising Flavia W. de Faria Daniel Münter Marc van de Wetering Kornelius Kerl Evelien Duiker Marius C. van den Heuvel Vincent E. de Meijer Ruben H. de Kleine Jan J. Molenaar Thanasis Margaritis Hendrik G. Stunnenberg Ronald R. de Krijger József Zsiros Hans Clevers Weng Chuan Peng Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids Nature Communications |
| title | Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids |
| title_full | Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids |
| title_fullStr | Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids |
| title_full_unstemmed | Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids |
| title_short | Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids |
| title_sort | divergent wnt signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids |
| url | https://doi.org/10.1038/s41467-024-52757-w |
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