A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma

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 and Roel Nusse ()
Additional contact information
Peng V. Wu: Stanford University School of Medicine
Matt Fish: Stanford University School of Medicine
Florette K. Hazard: Stanford University School of Medicine
Chunfang Zhu: Stanford University School of Medicine
Sujay Vennam: Stanford University School of Medicine
Hannah Walton: Stanford University School of Medicine
Dhananjay Wagh: Stanford University
John Coller: Stanford University
Joanna Przybyl: Stanford University School of Medicine
Maurizio Morri: Chan Zuckerberg Biohub
Norma Neff: Chan Zuckerberg Biohub
Robert B. West: Stanford University School of Medicine
Roel Nusse: Stanford University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-53802-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53802-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-53802-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().