PhD student – Modelling Embryonal Brain Tumors with BCOR alterations for Understanding Biology and Therapy Development

The research project

Extensive molecular characterization has identified many novel pediatric brain tumor types over the last decade. Although not always histologically distinguishable, they present with unique clinical, genomic and transcriptomic features. This molecular classification has improved diagnosis and risk stratification, but not patient survival, as effective therapies are still lacking.

One of these novel tumor types, which we discovered, are embryonal brain tumors with BCOR alterations. Most of these tumors harbor internal tandem duplication (ITD) or gene fusions affecting BCL6 corepressor (BCOR), a POZ/zinc finger transcription repressor, or its homologue BCORL1. Based on the normal function of these genes, these aberrations will alter their role in transcriptional and epigenetic regulation. Together with our international collaborators, the first patient-derived in vitro and in vivo models were generated. Furthermore, our lab routinely generates various stem cell-derived brain organoids, in which we can introduce oncodriving events via electroporation of DNA plasmids. These genetically engineered brain tumor organoid (GEBTO) models can mimic human tumors.

To study tumor biology and to discover better treatment options for patients with embryonal brain tumors with BCOR alterations, you will further establish and fully characterize GEBTO models for BCOR alterations and patient-derived models on a molecular and histological level. Using these models together with (single cell) RNA-seq and (epi)genomic data of tumors and the developing human brain, you will investigate the potential cellular origin and elucidate how altered BCOR proteins function to induce tumors. Based on identified molecular pathways involved in these tumors and high-throughput drug screens on your models, you will aim to discover more effective drugs and improve the survival and quality of life for children with these tumors.

Your project is embedded in the overarching research program of our group and our international collaborations. While our group members will provide technical and bioinformatical support for your project, other researchers and clinicians in the Máxima will support you with their specific expertise. Furthermore, our collaborators abroad will provide you with their knowledge and skills.

Your profile

We are looking for an enthusiastic and highly motivated PhD candidate, who is eager to spearhead this project, with the following qualifications and skills:

• A Master of Science degree or equivalent in (molecular) biology, biomedical sciences, neurosciences, or related disciplines.
• Demonstrated experience of performing experiments in a laboratory. For instances, hands-on experience with cell culture, immunohistochemistry and imaging and molecular and genomics techniques.
• A strong motivation, attention to detail, flexibility, well-organized and good data management skills are critical.
• The ability to work independently as well as collaborative in multidisciplinary and multicultural research teams.
• Excellent English written and verbal communication skills.
• Knowledge about pathways regulation tumorigenesis and/or neurodevelopment is preferred, but not required.
• Knowledge about bioinformatics analyses with, for instance, R is very welcome, but not essential.

Your job offer

We offer you a temporary, full-time PhD-position for a total duration of 4 years (36 hours / 5 days a week) in our group. You will also have the opportunity to actively collaborate with various research groups at the Princess Máxima Center and abroad. You will initially be contracted for a period of 1 year, with a possible extension. Your gross monthly salary will start in FWG 45-6 with a salary of €3.523,- gross a month for a fulltime working week (36 hours). You also receive 8.33% holiday allowance and 8.33 % end-of-year bonus. The Princess Máxima Center operates according to the collective labor agreement ‘CAO ziekenhuizen’.

The Princess Máxima Center for Pediatric Oncology is a research hospital concentrating healthcare, research, and education of pediatric cancer in a single location in Utrecht. The institute aims to provide the highest level of care for all children with cancer and has the ambition to cure all children of cancer and improve quality of life. The center brings together the best possible care and scientific research, creating a unique interdisciplinary institute for pediatric oncology in Europe.

Our research group, headed by Prof Dr Marcel Kool together with Dr Jens Bunt, studies the (epi)genomics and transcriptomics of pediatric brain tumors and how to translate findings from these studies into novel therapies. More effective and less toxic therapies are urgently needed. For many types of childhood brain tumors, the survival is still very poor, and survivors suffer from serious long-term side effects caused by their intensive therapies. To develop such new therapies, we need better understanding of tumor development and biology as well as molecularly well-characterized preclinical models that represent the broad intra and inter-tumor heterogeneity.

We focus on ependymomas, medulloblastoma and rare embryonal and sarcomatous tumors of the brain, which includes embryonal brain tumors with BCOR alterations. Using (epi)genomic and (single cell) transcriptomic analyses of tumors and normal developing brain, we study tumor biology, tumorigenesis and the tumor environment. Utilizing organoid technology and recent advances in neuroscience, we are also generating advanced patient-derived models and genetically induced tumor models derived from brain organoids. We use these models to accelerate the translation of our biological findings to get more effective therapies for patients.