NKI PhD Program 2023

Benjamin Rowland Group | Unravelling the mechanisms that structure chromosomes

The Rowland lab is looking for a motivated PhD student who will join our international and interdisciplinary team.

Research in the Rowland lab is driven by our fascination for how molecular machines such as cohesin and condensin can enable some of the most basic chromosomal processes. This ranges from chromosome segregation in mitosis, to the DNA folding in interphase that controls gene expression and DNA repair. The lab uses an interdisciplinary approach that involves genetics, genomics, biochemistry and imaging.

We are looking for an enthusiastic team-player, who enjoys discussing science, and who shares our passion for chromosome biology. The precise nature of the project will be determined following conversations with the PhD student to find the project that best matches the specific interests of the PhD student.

Thijn Brummelkamp Group | Experimental genetics

Whereas accurate maps exist depicting biochemical pathways, equivalent charts do not exist for the genetic wiring of human cells. This lack of knowledge provides a rich ground for biological discovery. Our goal is to create genetic tools for human cells and to apply these to address important biological questions. Specifically, we use haploid human cells as a genetic model system and apply insertional mutagenesis to link genes to phenotypes (Brockmann et al, 2017). In the last years we have used this approach to find host factors for pathogens (Staring et al, 2017), to identify essential genes and synthetic lethal interactions (Blomen et al, 2015), and to search for new genes relevant for immunotherapy (Mezzadra et al, 2017).  

Currently we are using genetics in haploid human cells to discover missing enzymes in key cellular processes (Nieuwenhuis et al, 2017; Landskron et al, 2022) and to elucidate new signaling or metabolic pathways that may play a role in cancer. Integrated analysis of our growing genotype-phenotype database sheds light on the genetic regulatory mechanisms that control human cells.

We are looking for a highly enthusiastic PhD student to join our group. We provide a collaborative and ambitious research environment in the department of biochemistry at the Netherlands Cancer Institute.

Jacco van Rheenen Group | Development prevention strategies by studying early stages of tumorigenesis

Due to the Western lifestyle, the incidence of colorectal cancer is increasing yearly. This trend is especially prevalent among young individuals. Late-stage colorectal cancer poses significant challenges for treatment, making it crucial to prioritize prevention and find effective cures. Our objective is to develop prevention strategies by studying the early stages of tumorigenesis. We will focus on understanding the cellular and molecular mechanisms that enable mutant cells to survive and initiate early tumor growth.

Our laboratory has developed unique intravital microscopy technologies and fluorescent models to observe the behavior of individual cells in living mice. In this project, we will utilize these technologies to investigate the earliest phases of tumorigenesis, specifically focusing on the fate of mutant cells in healthy tissues. In addition to intravital microscopy, we will employ various other state-of-the-art technologies, including 3D imaging of cleared human and mouse tissues, imaging analysis, mouse genetics, organoid technology, and histological examination of patient samples.

While this is primarily a fundamental research project, the outcomes will have significant relevance for colorectal cancer patients. Therefore, whenever possible, we will seek collaborations with clinicians to ensure that any clinically significant findings are effectively utilized.

Tineke Lenstra group | Transcription dynamics in single cells

The main interest of the Lenstra lab is to understand the regulatory mechanisms and dynamics of eukaryotic transcription. Precise regulation of transcription is essential to ensure that the correct genes are expressed in the correct tissue at the correct time. Misregulation can result in diseases such as cancer. Understanding the molecular mechanisms that regulate transcription requires a dynamic view of the underlying process inside single cells. Such single-cell studies have shown that genes are transcribed in a highly dynamic manner, with bursts of transcription activity interspersed with periods of inactivity. In our lab, we use cutting-edge single-molecule microscopy techniques to directly visualize and quantify these transcriptional fluctuations inside single cells. In addition, we visualize the stochastic behavior of individual regulatory molecules, such as transcription factors, to understand how their transient DNA binding regulates transcription activation. We combine these microscopy methods with gene-specific and conditional perturbations, (single-cell) genomic experiments, single-molecule in vitro analyses, and computational approaches, using both budding yeast and mammalian cells as model systems. Using these techniques, the projects in the lab focus on understanding how transcription factors, cofactors, promoter and enhancer sequences and chromatin regulates transcription in a dynamic manner. Moreover, in collaboration with Jurgen Marteijns lab, we study the dynamics and fate of RNA polymerases when they encounter DNA damage during transcription.  To push the field forward, we are also developing novel single-molecule microscopy techniques and kinetic analysis tools. Overall, by visualizing transcription dynamics in single cells, we aim to gain mechanistic insight into eukaryotic gene expression regulation in both health and disease.

Bas van Steensel Group | Tackling gene regulation by innovative genomics approaches

Our lab is fascinated by genome biology and gene regulation. What does an interphase chromosome look like? How do transcription factors, enhancers and promoters talk to each other? How are all ~30,000 genes in our genome coordinately regulated? And how can this go wrong in cancer? Clearly, the underlying molecular mechanisms and regulatory networks are very complex. But we believe we are in a good position to tackle this complexity, because our lab has developed a suite of unique, powerful genomics tools.

First, we use massively parallel reporter assays in combination with advanced computational methods such as deep learning to unravel the regulatory logic of enhancers and promoters, and to measure and predict the impact of sequence variation in human genomes. Second, we have built libraries of reporters that enable us to monitor the activity of dozens of transcription factors in parallel, thus elucidating the architecture of regulatory networks. Third, we develop a scalable, broadly applicable technology to systematically scramble a genomic locus of interest, either by 'hopping' enhancers and promoters to hundreds of alternative positions, or by inducing random inversions and deletions.  This helps us to understand how the linear ordering of regulatory elements enables their functioning. Together, these tools place us in a unique position to unravel the multilayered regulation of gene expression in healthy and cancer cells.

Our lab is an interdisciplinary team of wet-lab and computational scientists. Several PhD projects are possible, as long as they (i) connect to other projects in the lab; (ii) fire up your enthusiasm, and (iii) match your talents.

Wilbert Zwart Group | Hormonal regulation, transcriptional control and epigenetics in cancer

The Zwartlab is specialized in hormonal regulation, transcriptional control and epigenetics in cancer. Our unique expertise involves a ‘full circle approach’, with most projects in the team spanning from clinical observation to mechanistic studies, discovery of novel biomarkers or therapeutic opportunities and back again to the clinic. Our main track record is on Androgen Receptor functioning in prostate cancer (Linder at al., 2022. Cancer Discovery; Pomerantz et al., 2020. Nature Genetics), Glucocorticoid Receptor signalling in lung cancer (Prekovic et al., 2021 Nature Communications) and Estrogen Receptor action in breast cancer (Severson et al. 2018 Nature Communications) and endometrial cancer (Droog et al., 2017 PNAS ).

As hormone receptors are acting through enhancer elements, we are particularly interested in enhancer-promoter interactions in 3D genomic space, identification of essential enhancers in tumor cell fitness, enhancer plasticity in tumor progression and the impact of somatic mutations on enhancer function. The PhD project is positioned on the intersection of wetlab functional genomics studies with bioinformatics, aimed to better understand how enhancer dynamics and hormone receptor action itself is changing upon cancer progression, and how such epigenetic plasticity contributes to acquired therapy resistance in cancer. Past experience in molecular biology and (epi)genomics is required, prior knowledge of bioinformatics and programming in R is a plus.

PhD students at the Netherlands Cancer Institute (NKI) will take part in the training program organized by the Oncology Graduate School Amsterdam (OOA): a collaboration between the NKI, the Amsterdam UMC, the University of Amsterdam and Vrije Universiteit Amsterdam.

The students follow the OOA training program consisting of courses, meet-the-expert sessions, and an annual retreat. The program includes in-depth courses on various topics in cancer research, as well as technical courses in English writing, biostatistics and -informatics, microscopy, and animal handling. Students with an insufficient background in cancer research can attend the Experimental Oncology course for Master students. PhD students will have the opportunity to meet experts in the field of oncology.

The annual PhD student retreat will focus entirely on the research of the PhD students themselves. First year students will present their work in the form of a poster, advanced students will give oral presentations. Importantly, students will be in charge of chairing sessions, monitoring discussions, and selecting who will win the prize for the best posters or presentations. In this way, the retreat provides not only an overview of the research in the OOA at an early stage of the student’s career, but also a training in presentation and interaction skills.

We hope to encourage translational interactions and bottom-up research, in which PhD students actively establish collaborations with other research groups, further strengthening scientific exchange between the Amsterdam oncology centers.

PhD students are free to enroll in another graduate school if this school provides a more suitable training program.

We believe that excellent science can only be of value when it is based on trust, transparency, fairness, and equal opportunity. In our institute, we want our research to be responsible, in all possible respects.

We realize that this is an ongoing process of learning and doing, which starts with fostering an open, collaborative, and critical research environment. Read more.