# Investigating YAP1 control of differentiation and metabolism in Hepatoblastoma

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $47,711

## Abstract

Project Summary
Hepatoblastoma (HB), the most common pediatric primary liver tumor, affects children from infancy to five years
of age. Surgical resection with adjuvant chemotherapy has saved many young lives. However, the five-year
survival rate remains at 70%, and is worse for children with unresectable tumors. Meeting the clinical need for
HB-targeted therapies requires a better understanding of how HB tumors are formed and maintained. The
transcriptional co-regulator YAP1 is hyper-activated in 79% of HB cases, and recent studies suggest that YAP1
and the Wnt/β-catenin pathway act together to initiate HB tumors. But is YAP1 required to maintain HB
tumorigenesis? Preliminary studies using a conditional mouse model of HB—driven by doxycycline-inducible
hyperactive YAP1S127A and constitutively-active β-catenin—suggest that YAP1 is essential for tumor
maintenance. In the presence of doxycycline, YAP1 is expressed, and mice develop HB tumors; withdrawing
doxycycline turns off YAP1, resulting in >90% tumor regression within 10 weeks. Transcriptional analyses
revealed that hepatocyte differentiation factors and liver metabolic genes were induced in regressing tumors.
The goal of this proposal is to understand how YAP1 dysregulates hepatocyte differentiation and reprograms
hepatocyte metabolism. Using a conditional mouse model of HB, Aim 1 will investigate how YAP1 regulates
critical hepatocyte differentiation factors—HNF4a and FoxA2—to maintain HB tumorigenesis. Genetic tests will
be used to determine whether HNF4a and FoxA2 are necessary or sufficient to promote tumor regression and
differentiation. Genomic and biochemical approaches will be used to assess binding and affinity of the YAP1-
TEAD complex to HNF4a and FoxA2 genes. Results from Aim 1 will provide insight into how YAP1 affects
differentiation status and may have important prognostic implications for HB patients. Aim 2 will investigate how
YAP1 maintains tumorigenesis by reprogramming hepatocyte metabolism. The glycolytic enzyme activity of
pyruvate kinase M2 (Pkm2) will be measured in YAP1-dependent tumors and during tumor regression in
conditional HB mice. RNA interference will be used to determine whether Pkm2 is required for YAP1-dependent
tumor maintenance. This aim will examine previously uncharacterized YAP1 and Pkm2 regulation of tumor
metabolism. Findings from this study will provide insight into the mechanisms of YAP1 in HB tumorigenesis and
may define new prognostic factors and druggable targets to treat children suffering from HB.

## Key facts

- **NIH application ID:** 10104463
- **Project number:** 5F30CA239483-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Jordan Leigh Smith
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $47,711
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104463

## Citation

> US National Institutes of Health, RePORTER application 10104463, Investigating YAP1 control of differentiation and metabolism in Hepatoblastoma (5F30CA239483-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10104463. Licensed CC0.

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