A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma
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.
Authors
- Peng Wu (ORCID: https://orcid.org/0000-0001-6565-0002)
- Maurizio Morri (ORCID: https://orcid.org/0009-0003-5577-4265)
- Joanna Przybył (ORCID: https://orcid.org/0000-0002-8162-5226)
- John A. Coller (ORCID: https://orcid.org/0000-0002-7528-1527)
- Florette K. Hazard (ORCID: https://orcid.org/0000-0002-1538-0937)
- Robert B. West (ORCID: https://orcid.org/0000-0002-8330-8283)
- Roel Nusse (ORCID: https://orcid.org/0000-0001-7082-3748)
- Norma Neff (ORCID: https://orcid.org/0000-0001-7141-5420)
- Chunfang Zhu (ORCID: https://orcid.org/0000-0002-6773-0820)
- Dhananjay Wagh (ORCID: https://orcid.org/0000-0002-6937-003X)
- Sujay Vennam (ORCID: https://orcid.org/0000-0001-6312-1238)
- Matt Fish
- Hannah Walton
Institutions
- New York City Health and Hospitals Corporation (US)
- Cincinnati Children's Hospital Medical Center (US)
- Howard Hughes Medical Institute (US)
- California Institute for Regenerative Medicine (US)
- McGill University Health Centre (CA)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Emergency University (US)
- Chan Zuckerberg Initiative (United States) (US)
- Stanford Medicine (US)
- McGill University (CA)
- University of California, Davis (US)
- University of Cincinnati Medical Center (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1038/s41467-024-53802-4
- Citations
- 7
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Howard Hughes Medical Institute
- Burroughs Wellcome Fund
- Damon Runyon Cancer Research Foundation
- Virginia and D.K. Ludwig Fund for Cancer Research
- University of California, San Francisco
- Stanford Maternal and Child Health Research Institute