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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., Competing Interests: Competing interests: R.N. is a board member of Bio-Techne and a member of the Scientific Advisory Board of Surrozen Inc. The authors declare no other competing interests., (© 2024. The Author(s).)

Fibroblast Growth Factor 19 (FGF19) is a member of the Fibroblast Growth Factor (FGF) family, known for its role in various cellular processes including embryonic development and metabolic regulation. FGF19 functions as an endocrine factor, influencing energy balance, bile acid synthesis, glucose and lipid metabolism, as well as cell proliferation. FGF19 has a conserved structure typical of FGFs but exhibits unique features. Unlike most FGFs, which act locally, FGF19 travels through the bloodstream to distant targets including the liver. Its interaction with the β-Klotho (KLB) co-receptor and FGF Receptor 4 (FGFR4) in hepatocytes or FGFR1c in extrahepatic tissues initiates signaling cascades crucial for its biological functions. Although the mouse ortholog, FGF15, diverges significantly from human FGF19 in protein sequence and receptor binding, studies of FGF15-deficient mice have led to a better understanding of the proteins' role in bile acid regulation, metabolism, and embryonic development. Overexpression studies in transgenic mice have further revealed roles in not only ameliorating metabolic diseases but also in promoting hepatocyte proliferation and tumorigenesis. This review summarizes the gene and protein structure of FGF19/15, its expression patterns, phenotypes in mutant models, and implication in human diseases, providing insights into potential therapeutic strategies targeting the FGF19 signaling pathway., Competing Interests: Declaration of competing interest R.N. is a board member of Bio-Techne and a member of the Scientific Advisory Board of Surrozen Inc. The authors declare no other competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: As the most common pediatric primary liver cancer with rising incidence, hepatoblastoma remains challenging to treat. Here, we review the current understanding of the biology of hepatoblastoma and discuss how recent advances may lead to new treatment modalities., Recent Findings: Standard chemotherapy regimens including cisplatin, in addition to surgery, have led to high cure rates among patients with low stage hepatoblastoma; however, metastatic and relapsed disease continue to have poor outcomes. Recent genomics and functional studies in cell lines and mouse models have established a central role for the Wnt/β-catenin pathway in tumorigenesis. Targeted agents and immunotherapy approaches are emerging as potential treatment avenues. With recent gains in knowledge of the genomic and transcriptomic landscape of hepatoblastoma, new therapeutic mechanisms can now be explored to improve outcomes for metastatic and relapsed hepatoblastoma and to reduce the toxicity of current treatments., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatoblastoma, the most common primary liver malignancy in children, remains poorly understood due in part to a relative lack of methods to expand tumor cells in culture and a paucity of robust experimental models. Here, we describe a method to obtain primary tumor cells from patients with hepatoblastoma and to propagate the cells in 3D culture as tumor organoids, or "tumoroids". We further detail methods to prepare the tumoroids for whole-mount and cross-sectional imaging as well as to perform lentiviral transduction., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)