A Human Organoid Model of Aggressive Hepatoblastoma for Disease Modeling and Drug Testing.

James A Saltsman,Hans Clevers,Michael P Laquaglia,Nicole J C Narayan,Gadi Lalazar,Helmuth Gehart,Sanford Simon,David Requena,William J Hammond

doi:10.3390/cancers12092668

Abstract

Simple SummaryHepatoblastoma is the most common childhood liver cancer, making up over 90% of malignant liver tumors in children younger than 5 years of age. Currently, research to find new treatments for treatment-resistant hepatoblastoma is limited by a lack of appropriate models to study the disease. In this study, we describe a novel patient-derived organoid model of aggressive hepatoblastoma that can be used to study the disease in the laboratory and test new treatments. We demonstrate that tumor organoids share the same genomic profile as the patient tumors from which they are derived, and also demonstrate similar features with respect to gene expression profiles and beta-catenin signaling. We also demonstrate the feasibility of using hepatoblastoma organoids to complete a drug screen alongside normal liver control organoids derived from the same patient, and report promising initial results of anti-tumor activity of the BET inhibitor JQ1.Hepatoblastoma is the most common childhood liver cancer. Although survival has improved significantly over the past few decades, there remains a group of children with aggressive disease who do not respond to current treatment regimens. There is a critical need for novel models to study aggressive hepatoblastoma as research to find new treatments is hampered by the small number of laboratory models of the disease. Organoids have emerged as robust models for many diseases, including cancer. We have generated and characterized a novel organoid model of aggressive hepatoblastoma directly from freshly resected patient tumors as a proof of concept for this approach. Hepatoblastoma tumor organoids recapitulate the key elements of patient tumors, including tumor architecture, mutational profile, gene expression patterns, and features of Wnt/β-catenin signaling that are hallmarks of hepatoblastoma pathophysiology. Tumor organoids were successfully used alongside non-tumor liver organoids from the same patient to perform a drug screen using twelve candidate compounds. One drug, JQ1, demonstrated increased destruction of liver organoids from hepatoblastoma tumor tissue relative to organoids from the adjacent non-tumor liver. Our findings suggest that hepatoblastoma organoids could be used for a variety of applications and have the potential to improve treatment options for the subset of hepatoblastoma patients who do not respond to existing treatments.

Highlights

Hepatoblastoma is the most common childhood liver cancer, making up 80% of all malignant liver neoplasms in children, with over 90% of such lesions being in children younger than 5 years of age [1].The development of hepatoblastoma has been linked to environmental factors such as prematurity and genetic syndromes including Beckwith–Wiedemann syndrome [2]
We demonstrate that tumor organoids share similar gene expression patterns with other hepatoblastoma tumors, and that these transcriptomic profiles are unique from both normal tissue, and organoids derived from normal tissue
We have demonstrated that hepatoblastoma tumor organoids show morphologic similarity to the tumors from which they were derived, and retain genomic and transcriptomic alterations associated with the tumors

Summary

Introduction

Hepatoblastoma is the most common childhood liver cancer, making up 80% of all malignant liver neoplasms in children, with over 90% of such lesions being in children younger than 5 years of age [1].The development of hepatoblastoma has been linked to environmental factors such as prematurity and genetic syndromes including Beckwith–Wiedemann syndrome [2]. Survival for hepatoblastoma has improved significantly over the past few decades, there remains a group of children who experience poor outcomes, including death. These patients are not eligible for surgical resection and do not respond to current chemotherapy regimens. In order to develop improved therapies for such children, additional research is required to understand the biology of aggressive hepatoblastoma and perform targeted drug screening. Research of this nature is limited by the small number of in vitro models that accurately reflect the disease [7,8]. There is a specific dearth of models that reflect the aggressive subset of tumors that lead to the majority of deaths from hepatoblastoma [7]

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Results

Conclusion