Wu Lab
Understanding Hepatoblastoma in Children
The Wu Lab in the Division of Oncology seeks to understand how tumors initiate and grow during embryonic and early postnatal development, focusing on the liver and the most common primary liver cancer in children, hepatoblastoma (reviewed in Wu and Rangaswami, Current Oncology Reports 2022).
Our goal is to identify and elucidate the cell intrinsic and extrinsic signals that promote cancer growth during early development, using a combination of primary human tumoroids, tumor specimens, and mouse models.
Our mission is to unveil common paradigms that underlie the unique mechanisms of tumorigenesis of pediatric solid tumors as well as hepatobiliary carcinomas, to identify new therapeutic approaches for these cancers that remain challenging to treat.
Fig. 2. Confocal immunofluorescence in a hepatoblastoma tumoroid showing heterogeneous expression of hepatobiliary lineage markers, HNF4A (red, hepatocytic) and CK19 (green, cholangiocytic).
Fig 3. RNAscope in situ hybridization in a primary human hepatoblastoma specimen showing focal expression of FGF19 (red) in a subset of Wnt-activated tumor cells, marked by expression of AXIN2 (blue).
A major barrier in pediatric liver cancer research has been a relative lack of cell lines and models for the disease, due to its rarity and prior technical challenges with culturing these cells. We have developed a method of isolating primary human hepatoblastoma cells and propagating them long-term as 3D tumor organoids, or “tumoroids” (Fig. 1, Wu and Nusse, Methods in Molecular Biology 2022), generating a compendium of patient-derived cell models that can be used to study biology and test drugs.
Using these tumoroids, along with histology-guided and spatial transcriptomics of patient specimens, we determined that hepatobiliary lineage programs (Fig. 2) modify the transcriptional outcome of somatic mutations in the CTNNB1 gene, encoding the Wnt effector beta-catenin, found in up to 90% of hepatoblastomas (Wu et al., Nature Communications 2024).
We identified the growth factor, FGF19, as a downstream target of Wnt/beta-catenin and the embryonic biliary transcription factor, SOX4, cooperating with Wnt activation to promote cell cycle progression of hepatoblastoma cells (Fig. 3).
Our ongoing work focuses on further elucidating how hepatobiliary lineage programs and developmental growth signals interact to promote tumorigenesis in hepatoblastoma.
Meet the PI
Peng V. Wu, MD, PhD
While my interest in combining cancer research with patient care developed early through my undergraduate studies and research experiences, I was drawn to pediatrics and pediatric oncology during my clinical rotations in medical school. As a physician-scientist, I was particularly inspired by the advances made in treating childhood cancers while recognizing the persistent challenges and opportunities to apply my scientific training to improve care for this vulnerable patient population.
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