A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma
Abstract Cancers evolve not only through the acquisition and clonal transmission of somatic mutations but also by epigenetic mechanisms that modify cell phenotype. Here, we use histology-guided and spatial transcriptomics to characterize hepatoblastoma, a childhood liver cancer that exhibits signifi...
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| Format: | Article |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53802-4 |
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| author | Peng V. Wu Matt Fish Florette K. Hazard Chunfang Zhu Sujay Vennam Hannah Walton Dhananjay Wagh John Coller Joanna Przybyl Maurizio Morri Norma Neff Robert B. West Roel Nusse |
| author_facet | Peng V. Wu Matt Fish Florette K. Hazard Chunfang Zhu Sujay Vennam Hannah Walton Dhananjay Wagh John Coller Joanna Przybyl Maurizio Morri Norma Neff Robert B. West Roel Nusse |
| author_sort | Peng V. Wu |
| collection | DOAJ |
| description | Abstract Cancers evolve not only through the acquisition and clonal transmission of somatic mutations but also by epigenetic mechanisms that modify cell phenotype. Here, we use histology-guided and spatial transcriptomics to characterize hepatoblastoma, a childhood liver cancer that exhibits significant histologic and proliferative heterogeneity despite clonal activating mutations in the Wnt/β-catenin pathway. Highly proliferative regions with embryonal histology show high expression of Wnt target genes, the embryonic biliary transcription factor SOX4, and striking focal expression of the growth factor FGF19. In patient-derived tumoroids with constitutive Wnt activation, FGF19 is a required growth signal for FGF19-negative cells. Indeed, some tumoroids contain subsets of cells that endogenously express FGF19, downstream of Wnt/β-catenin and SOX4. Thus, the embryonic biliary lineage program cooperates with stabilized nuclear β-catenin, inducing FGF19 as a paracrine growth signal that promotes tumor cell proliferation, together with active Wnt signaling. In this pediatric cancer presumed to originate from a multipotent hepatobiliary progenitor, lineage-driven heterogeneity results in a functional growth advantage, a non-genetic mechanism whereby developmental lineage programs influence tumor evolution. |
| format | Article |
| id | doaj-art-2d94ec01e9d046b7b6d307f07deb9f1b |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-2d94ec01e9d046b7b6d307f07deb9f1b2024-11-24T12:32:34ZengNature PortfolioNature Communications2041-17232024-11-0115111910.1038/s41467-024-53802-4A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastomaPeng V. Wu0Matt Fish1Florette K. Hazard2Chunfang Zhu3Sujay Vennam4Hannah Walton5Dhananjay Wagh6John Coller7Joanna Przybyl8Maurizio Morri9Norma Neff10Robert B. West11Roel Nusse12Howard Hughes Medical Institute, Stanford University School of MedicineHoward Hughes Medical Institute, Stanford University School of MedicineDepartment of Pathology, Stanford University School of MedicineDepartment of Pathology, Stanford University School of MedicineDepartment of Pathology, Stanford University School of MedicineHoward Hughes Medical Institute, Stanford University School of MedicineStanford Genomics, Stanford UniversityStanford Genomics, Stanford UniversityDepartment of Pathology, Stanford University School of MedicineChan Zuckerberg BiohubChan Zuckerberg BiohubDepartment of Pathology, Stanford University School of MedicineHoward Hughes Medical Institute, Stanford University School of MedicineAbstract Cancers evolve not only through the acquisition and clonal transmission of somatic mutations but also by epigenetic mechanisms that modify cell phenotype. Here, we use histology-guided and spatial transcriptomics to characterize hepatoblastoma, a childhood liver cancer that exhibits significant histologic and proliferative heterogeneity despite clonal activating mutations in the Wnt/β-catenin pathway. Highly proliferative regions with embryonal histology show high expression of Wnt target genes, the embryonic biliary transcription factor SOX4, and striking focal expression of the growth factor FGF19. In patient-derived tumoroids with constitutive Wnt activation, FGF19 is a required growth signal for FGF19-negative cells. Indeed, some tumoroids contain subsets of cells that endogenously express FGF19, downstream of Wnt/β-catenin and SOX4. Thus, the embryonic biliary lineage program cooperates with stabilized nuclear β-catenin, inducing FGF19 as a paracrine growth signal that promotes tumor cell proliferation, together with active Wnt signaling. In this pediatric cancer presumed to originate from a multipotent hepatobiliary progenitor, lineage-driven heterogeneity results in a functional growth advantage, a non-genetic mechanism whereby developmental lineage programs influence tumor evolution.https://doi.org/10.1038/s41467-024-53802-4 |
| spellingShingle | Peng V. Wu Matt Fish Florette K. Hazard Chunfang Zhu Sujay Vennam Hannah Walton Dhananjay Wagh John Coller Joanna Przybyl Maurizio Morri Norma Neff Robert B. West Roel Nusse A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma Nature Communications |
| title | A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma |
| title_full | A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma |
| title_fullStr | A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma |
| title_full_unstemmed | A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma |
| title_short | A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma |
| title_sort | developmental biliary lineage program cooperates with wnt activation to promote cell proliferation in hepatoblastoma |
| url | https://doi.org/10.1038/s41467-024-53802-4 |
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