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

Abstract

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.

Patient-Derived Cancer Organoids as Predictors of Treatment Response

“…For one patient drug testing was performed on the matched normal liver and tumor organoids. This screen identified one drug (JQ1) to have an increased efficacy on tumor organoids compared to normal organoids whereas standard-of-care cisplatin had not differential effect ( 42 ). Matched normal liver tissue organoids were also developed by others, providing opportunities to test normal tissue toxicity ( 32 ).…”

Organoids in cancer research: a review for pathologist‐scientists

“…This has provided enriched neoplastic cell populations for molecular analysis but could also be used in the future to interrogate a variety of cellular and molecular questions in premalignant neoplasia. Organoids can also be used as in vitro models for rare tumor types for which no or limited 2D cell line models exist, such as hepatoblastoma [43] or pediatric kidney cancer [44]. Organoid models have even been used to culture unique animal cell types, such as cells from snake venom glands [45], demonstrating the versatility and potentially far‐reaching use of the model.…”

Modeling the developmental origins of pediatric cancer to improve patient outcomes

“…This method has produced models of pediatric cancers including medulloblastoma ( Huang et al, 2019 ) and retinoblastoma ( Saengwimol et al, 2018 ). For some cancers, such as hepatoblastoma ( Saltsman et al, 2020 ) and Wilms tumor of the kidney ( Calandrini et al, 2020 ), tumor-derived cells have been used to develop organoids exhibiting multilineage potential.

James F. Amatruda, MD, PhD.

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