Cancer is still one of the leading causes of disease-related deaths in children. Survivors suffer from side effects of the, in most cases, intensive treatment regimens. Hence, there is an urgent need to develop improved, less toxic therapies. Our vision is that if we understand the processes that underpin the development of childhood cancer, we will facilitate improved cure rates and a better quality of life. However, therapeutic innovation is hampered by the lack of cell models representative of native tumor tissue. We are convinced that by developing cancer models that more closely recapitulate the patient's tumor, we will be able to more efficiently translate pre-clinical findings to the clinic and bridge the gap between bench and bedside: Better models, increased knowledge: more cures!
Organoids as representative models of childhood solid tumors
The organoid technology has revolutionized cancer research, as it allows for the ‘unlimited’ expansion of healthy and diseased tissue from individual patients in a dish, while retaining essential characteristics of native tissue. Organoids are therefore seen as avatars of the tissue they were derived from. The Drost group pioneered the use of organoid technology for pediatric cancer research. We succeeded in establishing culture protocols to grow organoids from a wide spectrum of pediatric malignancies such as Wilms tumors, renal cell carcinomas, as well as different rhabdoid tumor and soft tissue sarcoma subtypes. We use these models to study the very fundamental processes underlying tumorigenesis (see below), as well as for more translational research projects. For instance, we use the organoids as drug screen platform to find tumor-specific drug vulnerabilities, but we also develop co-culture systems of organoids and different types of immune cells to explore the use of immunotherapy in pediatric cancer.
Defining the developmental origin of childhood cancers
Many childhood tumors already originate in the developing fetus, but their cellular origin remains in many cases unknown. Finding the tumor’s cell-of-origin will provide important clues into what has caused its development e.g., a block in differentiation. Relieving such a block pharmacologically would be an attractive therapeutic intervention (so-called maturation therapy).
To find the origin of tumors, we make use of different approaches. First, we apply DNA sequencing technologies to find phylogenetic relations between tumors and normal tissues of the same individual. To do so, we use somatic mutations as “barcodes” to trace back the origin of the tumor. Second, we make use of (single-cell) transcriptome and epigenome sequencing approaches, as we and others have shown that embryonal tumors mirror features of their cells-of-origin to a large extend. By comparing tumor transcriptomes with the transcriptomes of fetal tissue development, we aim to unravel the tumor’s cellular identity.
Studying the (epigenetic) processes driving tumor initiation and progression
The pediatric cancer organoid models that we have established give us the unique opportunity to study the processes driving tumor initiation, progression, and therapy resistance. We are particularly interested in the epigenome changes occurring in pediatric tumors uniquely defined by mutations in SWI/SNF complex members. By using tumor organoids in combination with gene editing technologies and (single-cell) omics read-outs, we aim to pinpoint the tumor-driving signaling pathways that could serve as therapeutic targets. Furthermore, we have developed orthotopic organoid xenograft models and barcode lineage tracing strategies that allow us to study clonal dynamics during the different steps of tumorigenesis (such as primary tumor growth, metastasis formation, and therapy resistance) in great detail.
Besides tumor organoids, we use healthy tissue-derived organoids for the generation of tumor models. We apply different genome editing technologies (such as CRISPR/Cas9 technology) to healthy organoids to generate tumor progression models. Such engineered tumor organoids provide genetically defined models that allow for studying the contribution of specific genetic alterations to tumorigenesis.