PhD candidate Pathogenesis of stem cells tumorigenicity (1.0 FTE)

Human embryonic stem cells and induced pluripotent stem cells can be maintained in culture indefinitely (self-renewal) and differentiate into virtually all cell types of the human body (pluripotency). Challenges in stem cell therapies include the detection and removal of incompletely differentiated cells, addressing the genomic and epigenetic alterations in the generated cells and overcoming the tumorigenicity of these cells that could arise on transplantation. Moreover, long-term culture of PSCs can lead to (epi)genetic drift, potentially activating processes that resemble malignant transformation as an adaptive mechanism to the culture conditions.

Indeed, the malignant potential of human pluripotent stem cells is not fully understood, and its evaluation currently relies solely on the assessment of the cells’ behaviour in vivo upon their engraftment into mouse models (teratoma assay). Our group is currently working on in vitro models able to answer the malignancy question. Stem cells are also key to normal development and health from conception through adulthood. Stem cells survive much longer than ordinary cells, increasing the chance that they might accumulate genetic mutations. It might take only a few mutations for one cell to lose control over its self-renewal and growth and become the source of cancer.

You are going to study the mechanism of oncogenic transformation, supporting the potential value of studying this aspect in the context of pathogenesis, clinical handling, and treatment of human malignant germ cell tumors and vice versa. Focus will be given to the role yolk sac in tumors derived from stem cells and in human germ cell tumors. Yolk sac tumors can be found in a pure form or mixed with other germ cell tumors. They are common in the pediatric age group and can be found anywhere in the body. Yolk sac tumors are a major histological subtype of malignant germ cell tumors with a relatively poor prognosis. This topic will therefore include studying mechanisms of drug resistance. Also in stem cells derived tumors, yolk sac presence is associated with malignancy. You will explore further the use of liquid biopsies (miRNAs) to identify malignancy in vivo and in vitro.

You will be embedded in Salvatori’s group (Regenerative Medicine Utrecht and Veterinary Faculty) and you will work closely with the group led by Prof Leendert Looijenga, Princess Máxima Centrum.

Used techniques will include:

• cell culture of stem cells, including 3D cultures and 3D culture assays; organoids
• microRNA analysis
• single cell analysis including bioinformatic tools
• generation of induced pluripotent stem cell lines using CRISPR/Cas9 system
• histology, advanced microscopy, FACS

Qualifications
We are looking for a creative and independent thinker who can deepen a research question, an enthusiastic and energetic communicator (both oral and written) and a team player. You will join an international team, therefore fluency in English is required. Your findings will be published in peer reviewed journals and you will present your work in the department and at international conferences.

Experience in cancer research, molecular and cellular biology, and within vitro models such as stem cells/organoids will be an advantage.

A better future for everyone. This ambition motivates our scientists in executing their leading research and inspiring teaching. At Utrecht University, the various disciplines collaborate intensively towards major strategic themes. Our focus is on Dynamics of Youth, Institutions for Open Societies, Life Sciences and Sustainability.

The Faculty of Veterinary Medicine of Utrecht University is the only Veterinary School in the Netherlands. It belongs to the international top in education, research and veterinary patient care. The faculty counts approximately 1,500 students and 1,000 employees. It organizes its research activities via an Institute of Veterinary Research and participates in the university-wide research programme “Life Sciences”. The faculty also provides academic training for veterinarians, researchers and trainee specialists and is located at Utrecht Science Park near the historical city centre of Utrecht. Watch Radiotherapy at the Academic Veterinary Hospital for an impression (in Dutch).

The PhD candidate will work closely with the group led by Prof Leendert Looijenga, Princess Máxima Centrum.