HepT1-derived murine models of high-risk hepatoblastoma display vascular invasion, metastasis, and circulating tumor cells

Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal t...

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Bibliographic Details
Published in:Biology open 2022-09, Vol.11 (9)
Main Authors: Woodfield, Sarah E, Mistretta, Brandon J, Patel, Roma H, Ibarra, Aryana M, Fisher, Kevin E, Sarabia, Stephen F, Gandhi, Ilavarasi, Reuther, Jacquelyn, Starosolski, Zbigniew, Badachhape, Andrew, Epps, Jessica, Zorman, Barry, Shah, Aayushi P, Larson, Samuel R, Srivastava, Rohit K, Shi, Yan, Espinoza, Andres F, Govindu, Saiabhiroop R, Whitlock, Richard S, Holloway, Kimberly, Roy, Angshumoy, Sumazin, Pavel, Ghaghada, Ketan B, Lopez-Terrada, Dolores, Gunaratne, Preethi H, Vasudevan, Sanjeev A
Format: Article
Language:English
Subjects:
Animal models
Blood vessels
circulating tumor cell
DNA sequencing
Flow cytometry
Gene expression
hepatoblastoma
Immunohistochemistry
Injection
invasion
Liver
Liver cancer
Magnetic resonance
Magnetic resonance imaging
Malignancy
Metastases
Metastasis
mouse model
Mutation
pediatric liver cancer
Pediatrics
Ribonucleic acid
Risk
RNA
Transcriptomics
Tumor cell lines
Tumor cells
Tumors
Veins
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Summary:Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB.
ISSN:2046-6390
2046-6390
DOI:10.1242/bio.058973