Abstract C017: Patient-Derived iPSC Liver Organoids Model Embryonal Hepatic Reprogramming and Collagen IV-Integrin Signaling in BWS-Associated Hepatoblastoma
Snehal Nirgude, Madison Newsome, Elisia Tichy, Khanh B. Trang, Jennifer M. KalishAbstract
Background:
Beckwith-Wiedemann syndrome (BWS) is a cancer predisposition disorder caused by epigenetic alterations at chromosome 11p15, which confers increased risk of hepatoblastoma in early childhood. The mechanisms linking 11p15 dysregulation to tumor initiation remain unclear. Building on our previously published single-nucleus multiomic analyses of BWS-associated hepatoblastoma, we developed a multicellular patient-derived induced pluripotent stem cell (iPSC) liver organoid model system, including isogenic controls, to interrogate developmental and microenvironmental programs underlying tumor initiation.
Methods:
Previously published snRNA-seq and snATAC-seq datasets from BWS (n=4) and non-BWS (n=3) hepatoblastomas and matched tumor-adjacent liver tissues were integrated with analyses of multicellular BWS patient-derived iPSC liver organoids and their isogenic control organoids. Trajectory analysis (Slingshot) and ligand-receptor inference (CellChat) identified developmental and extracellular matrix (ECM) programs associated with early tumorigenesis in liver tissues. Correspondingly, gene expression of key pathways was quantified in organoids by qPCR across ≥2 independent differentiations per line (n=50 organoids/condition). Statistics were performed on biological replicate means using two-sided t-tests with FDR correction.
Results:
Multiomic analyses showed that BWS hepatoblastomas are dominated by a predominantly embryonal transcriptional program and cellular heterogeneity. Trajectory analysis identified a distinct transition hepatocyte population in BWS liver with intermediate transcriptomic and epigenomic states between normal hepatocytes and hepatoblastoma, enriched for ECM-receptor interaction and gap junction signaling, consistent with a pre-neoplastic state. Ligand-receptor analysis revealed enhanced type IV collagen signaling among stellate, endothelial, and hepatocyte populations, supporting formation of an embryonal extracellular matrix niche during early tumorigenesis. Multicellular BWS iPSC-derived liver organoids containing hepatocytes, cholangiocytes, hepatic stellate cells, and endothelial cells successfully recapitulated these molecular features. Compared with isogenic controls, BWS organoids exhibited a ≥1.5-fold increased expression of the embryonal marker GPC3 (P < 0.05) and coordinated ≥1.5-fold upregulation of LAMB1, COL4A1, COL4A2, ITGA1, and ITGB1 (all P < 0.05), consistent with activation of a collagen IV-integrin axis observed in patient tissues.
Conclusions:
These findings support a model in which BWS-associated hepatoblastoma arises through developmental reprogramming toward an embryonal hepatic state coupled with remodeling of a collagen IV-rich ECM, forming a niche permissive for tumor initiation. Integration of human multiomic datasets with multicellular patient-derived iPSC liver organoid models provides a physiologically relevant system to study early hepatoblastoma development and supports ECM-integrin signaling as a candidate axis for biomarker development and early intervention in children with BWS.
Citation Format:
Snehal Nirgude, Madison Newsome, Elisia Tichy, Khanh B. Trang, Jennifer M. Kalish. Patient-Derived iPSC Liver Organoids Model Embryonal Hepatic Reprogramming and Collagen IV-Integrin Signaling in BWS-Associated Hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr C017.