A Human Organoid Model of Aggressive Hepatoblastoma for Disease Modeling and Drug Testing
by
, ,
James A. Saltsman
1,2, 
William J. Hammond
1,2,†
,
Nicole J. C. Narayan
1,2,†,
David Requena
1,†
,
Helmuth Gehart
3,
Gadi Lalazar
1,
Michael P. LaQuaglia
2,
Hans Clevers
3,4 and 
Sanford Simon
1,* 1
Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
2
Pediatric Surgery Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
3
Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands
4
The Princess Maxima Center for Pediatric Oncology, 3584CT Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this paper.
Cancers 2020, 12(9), 2668; https://doi.org/10.3390/cancers12092668
Submission received: 5 August 2020
/
Revised: 1 September 2020
/
Accepted: 15 September 2020
/
Published: 18 September 2020
(This article belongs to the Section Methods and Technologies Development)
Simple Summary
Hepatoblastoma 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.
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.
