PhD candidate 'Zebrafish model for paragangliomas’

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from the adrenal medulla or sympathetic ganglia, respectively. Currently, there is no effective treatment for patients with metastatic or inoperable PPGLs. Patients with mutations in the β-subunit of the succinate dehydrogenase (SDHB) have the highest risk to develop incurable malignant PPGLs.

Therapy development is severely hampered by the limited availability of suitable model systems. The succinate dehydrogenase (SDH) complex has a major role in tumorigenesis, which we try to further unravel using zebrafish as animal model organism. We generated a first vertebrate animal model that mimics the metabolic effects of SDHB-associated PPLGs which allows us for the first time to study the metabolic effects of the lack of sdhb in vivo. This larval model will we used as powerful drug screening tool to provide valuable insights into pathomechanisms. In parallel, the adult fish will be used as functional tumor model. For this, a comprehensive toolbox for tumor detection and follow tumor growth in our sdhbrmc200 zebrafish model is ready for use.

In this project, strategies will be applied to accelerate tumor development in adult zebrafish to unravel underlying pathogenic mechanisms and to evaluate therapeutic strategies in vivo. You will develop and apply new tools to study and accelerate the process of tumorigenesis in adult zebrafish. In parallel, the obtained data will be compared and validated in available human samples. The role of especially the immune system, epigenetics, oxidative stress and DNA repair will be studied in detail. Ultimately, you will explore the potential of new therapeutic targets to treat malignant SDHB-associated PPGLs.

Tasks and responsibilities

• Characterization of inter-renal tumor formation in systemic and tissue-specific sdhb mutant zebrafish.
• Application and development of aggravation strategies to induce tumor formation in adult zebrafish.
• Investigating the role of oxidative stress, DNA repair, epigenetics and the immune system in tumorigenesis.
• Identification of novel therapeutic targets and drugs.
• Comparison and validation of zebrafish data with available human samples.
• Generate and critically analyse the data in order to contribute to scientific publications and presents findings at scientific meetings.
• Work in a highly international research group with fellows from many countries.
• Supervise MSc and/or BSc students.
• Write and defend a PhD thesis within three years of starting the project.
• Participation in the graduate school of Radboudumc.