1. A Human Organoid Model of Aggressive Hepatoblastoma for Disease Modeling and Drug Testing
- Author
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Sanford M. Simon, Helmuth Gehart, James A. Saltsman, Nicole J.C. Narayan, William J. Hammond, Gadi Lalazar, David Requena, Hans Clevers, Michael P. LaQuaglia, and Hubrecht Institute for Developmental Biology and Stem Cell Research
- Subjects
0301 basic medicine ,Drug ,Cancer Research ,Hepatoblastoma ,pediatrics ,media_common.quotation_subject ,Disease ,Aggressive disease ,lcsh:RC254-282 ,Article ,liver cancer ,03 medical and health sciences ,0302 clinical medicine ,3-D culture ,medicine ,Organoid ,organoids ,media_common ,business.industry ,Wnt signaling pathway ,Cancer ,sequencing ,pediatric oncology ,hepatoblastoma ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,digestive system diseases ,030104 developmental biology ,pediatric solid tumor ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Liver cancer ,business - 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/&beta, 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.
- Published
- 2020
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