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.

癌症不仅通过体细胞突变的获得和克隆传递而进化，还通过改变细胞表型的表观遗传机制进化。在这里，我们使用组织学引导和空间转录组学来表征肝母细胞瘤，这是一种儿童肝癌，尽管 Wnt/β-catenin 通路中存在克隆激活突变，但仍表现出显着的组织学和增殖异质性。具有胚胎组织学的高度增殖区域显示 Wnt 靶基因、胚胎胆汁转录因子 SOX4 的高表达和生长因子 FGF19 的显著局灶性表达。在具有组成型 Wnt 激活的患者来源的类肿瘤中，FGF19 是 FGF19 阴性细胞所需的生长信号。事实上，一些类肿瘤包含内源性表达 FGF19 的细胞亚群，位于 Wnt/β-catenin 和 SOX4 的下游。因此，胚胎胆道谱系程序与稳定的核 β-catenin 合作，诱导 FGF19 作为促进肿瘤细胞增殖的旁分泌生长信号，以及活跃的 Wnt 信号传导。在这种推测起源于多能肝胆祖细胞的小儿癌症中，谱系驱动的异质性导致功能生长优势，这是一种发育谱系程序影响肿瘤进化的非遗传机制。