# Modeling Hepatoblastoma using pluripotent stem cell derived hepatocyte-like cells

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $382,700

## Abstract

Project Summary/Abstract
Hepatoblastoma is the most common liver neoplasm in children and accounts for approximately 1% of all
childhood malignancies. Five-year survival for hepatoblastoma is 59-74%; one of the lowest survival rates for
childhood cancer and is dictated largely by surgical control. Therefore, an improved understanding of the
mechanisms underlying this cancer will enable the development of improved and more targeted clinical
therapies. Hepatoblastoma is an embryonal tumor with distinct phenotypes and whose classification and
treatment is guided largely by both histology and immunohistochemical staining. The molecular defects present
in hepatoblastoma have been identified but their testing and inclusion of targeted therapies into clinical therapy
have not been adopted and consequently curative treatment largely consists of surgery alone. Our central
hypothesis is that the most common mutation present in hepatoblastoma tumors, CTNNB1 cause
differentiation defects, increased cellular proliferation, and tumorigenesis in a cell-specific manner. Therefore,
the lack of robust models of hepatoblastoma in a relevant and appropriate cell type has significantly impaired
our ability to better understand the molecular underpinnings underlying this cancer and to develop improved
and effective clinical therapies. These tumors have relative genetic simplicity, consequently we can readily
generate cell lines containing genetically similar and relevant mutations. We propose to use induced
pluripotent stem cells (PSC) and PSC derived hepatoblasts and hepatocyte-like cells engineered using CrispR
technology to generate mutations in β-catenin, the most common gene that is mutated in hepatoblastoma. In
our preliminary data, we have used CrispR/Cas9 technologies to generate human PSC lines with similar
mutations in CTNNB1. These PSC lines have increased activation of WNT signaling but differentiate normally
into hepatoblast-like cells, at which point, these cells proliferate and have differentiation defects. Mutant
CTNNB1 containing hepatoblasts and hepatocyte-like cells form tumors in vivo. The proposed work will
determine the role that mutant CTNNB1 plays in driving hepatoblastoma formation. We will study CTNNB1-
mutant containing PSC derived hepatoblasts and hepatocyte-like cells and determine the effect of mutant
CTNNB1 on cellular differentiation, proliferation, the transcriptomic and metabolomic signature, and
tumorigenesis in vivo. We will then use inducible Cas9 platforms to dynamically generate mutations to
determine whether the developmental stage at which CTNNB1 mutations form leads to further downstream
alterations in cellular differentiation, phenotype, and tumorigenesis. Finally we will determine whether the
timing and order of coincident mutations in addition to the specific types of cells in which the mutations are
generated impacts hepatoblastoma formation. The dissection of key regulators of hepatoblastoma formation
will enable us to id...

## Key facts

- **NIH application ID:** 10489684
- **Project number:** 5R01CA234614-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Robert E Schwartz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,700
- **Award type:** 5
- **Project period:** 2019-08-19 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489684

## Citation

> US National Institutes of Health, RePORTER application 10489684, Modeling Hepatoblastoma using pluripotent stem cell derived hepatocyte-like cells (5R01CA234614-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10489684. Licensed CC0.

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