Our Research

Childhood liver cancer

Each year, 8 to 10 children in the Netherlands are diagnosed with liver cancer, a number that is rising partly due to an increase in premature births. Among these young patients, the most prevalent tumor types are hepatoblastoma and hepatocellular carcinoma. Hepatoblastoma presents in various histological subtypes, including the more differentiated fetal subtype and the more undifferentiated embryonal subtype. In contrast, hepatocellular carcinomas in adolescents display distinct pathological and biological characteristics, compared to hepatoblastoma. The rarity of childhood liver cancers poses significant challenges for research, highlighting the need for dedicated studies on this specific patient population.

Metabolic liver disease

We are particularly interested in investigating metabolic liver diseases, as these hereditary conditions often predispose individuals to hepatocellular carcinoma in adolescence and young adulthood. These rare diseases, often caused by single gene defects, can lead to severe liver dysfunction. While liver transplantation is often the only curative option, it poses significant challenges including shortage of donor organs and the risk for rejection, underscoring the need for innovative treatment modalities.

Liver regeneration

The liver is a remarkable organ known for its unparalleled regenerative capabilities in the human body. Liver regeneration is a complex and well-coordinated physiological process crucial for maintaining homeostasis and ensuring survival after significant injury. This process allows the liver to recover its mass and function while preserving its structure and organization. Understanding the intricacies of liver regeneration will provide critical insights into development of treatments for liver diseases.

Therapeutics innovation

Omics meets organoids

We use data- and model- driven approaches to innovate therapeutics development. We aim to find tumor-specific therapeutic strategies to treat liver cancer patients, exposing fewer children to high-doses of chemotherapy, and ultimately curing more children without compromising their quality of life. Potential novel treatment avenues for these patients include immunotherapies, antibody therapies, and small molecule inhibitors. For metabolic liver disease patients potential treatments can be searched in gene editing, RNA-therapeutics and cell replacement therapies.

Primary hepatocyte organoids

Mature hepatocytes, including diploid and polyploid cells, can be induced to proliferate, without the need for stem cells. In 2018, we were the first to demonstrate that mouse hepatocytes, the major cell type in the liver, can be propagated indefinitely in 3D organoid cultures, by employing factors that are associated with tissue repair. Of particular significance is that hepatocyte organoids can efficiently engraft into the injured livers of mice and restore liver function. The ability to generate large number of stem cells is the first essential step towards making cell replacement therapy possible in patients with liver disease, potentially addressing the global challenge of organ donor shortages. We are also actively engaged in the development of more advanced organoid models.

Metabolic liver disease organoids

We utilize these mouse hepatocyte organoids to model inherited metabolic liver diseases using CRISPR-Cas9 gene-editing technology. In addition, we also generate hepatocyte organoids from genetically engineered mouse models. These models not only provide insights into the development of the disease, but also allow for the testing of novel therapies, such as gene editing and RNA-based therapies.

Patient-derived tumor organoids

Given the rarity of childhood liver tumors, the patient-derived tumor organoid models established by our group are an invaluable resource for preclinical research. We were the first to establish an extensive cohort of patient-derived tumor organoid models from various disease stages of hepatoblastoma. These lab grown tumor cells are used for various studies, such as the modeling efficacy of engineered T cells, drug screening, gene editing and testing RNA-therapeutics. In addition, we contributed to the generation of organoids models for pediatric liver cancer as part of the ITCC-P4 consortium and the Dutch Oncode Accelerator foundation.

Single-cell and spatial omics

We are commited to uncovering the intricacies of liver pathologies through new technology. One of our main goals is to decipher the molecular heterogeneity of various pediatric tumor subtypes, pinpoint critical signaling pathways, and explore the tumor immune microenvironment. To achieve these objectives, we harness multiomic approaches, including single-cell analysis of the transcriptome and epigenome, spatial transcriptomics, high-plex imaging methods and label-free mass spectrometry-based proteomics.