1B. Genetically engineered brain tumour organoids for preclinical research

Extensive molecular characterization of pediatric brain tumors has identified many new clinically and molecular distinct tumor (sub)types, often characterized by tumor-specific oncodriving fusion genes or mutations. As a result, molecular classification has improved the accuracy of diagnosis and prognosis of pediatric brain tumors, but specific treatments for these novel tumor types is often still lacking. To develop effective and non-toxic treatment strategies we need molecularly well-characterized preclinical models representing the different subtypes. This project aims to generate such preclinical models, use them to study tumor biology and to test novel treatment strategies.

To accomplish this goal, human iPSC-derived brain organoids will be genetically modified with tumor specific mutations. This approach has been successful in our lab to induce tumors mimicking patient tumors. The oncogenicity of various oncodrivers will be determined by immunostaining and growth assays. Molecular profiling and histology will reveal the identity of these induced tumors. The generated long-term preclinical models from these organoids will be compared to patient tumors as well as patient-derived tumoroids and xenografts.

To better understand tumor biology and to discover potential targets for therapy, we will investigate the molecular and cellular changes caused by the specific oncodrivers. For instance, (single cell) RNA-sequencing and chromatin immunoprecipitation will reveal (direct) transcriptional targets, which will further be characterized in vitro to determine their role in normal development and tumorigenesis. To identify potential drugs for treatment, high-throughput or targeted drugs screens will be performed. Co-culturing induced tumors with normal brain organoids or immune cells will elucidate how tumor cells interact with their environment and whether immunotherapy might be feasible.

This project will determine the function of novel tumor-specific oncodrivers and thereby uncover tumor biology. It will deliver novel preclinical models for brain tumors currently lacking patient-derived models. Together, this will accelerate the development of more tumor-specific, effective and less toxic treatments.

Necessary skills for this position:

• Master of Science degree in (molecular) biology, biomedical sciences, neurosciences, or related disciplines.
• Proven laboratory experience, preferable with molecular and genomics techniques, cell culture, immunohistochemistry and/or imaging