Research Group MEDEMA

Faculty of Medicine, University Medical Centre Utrecht, Dept. of Medical Oncology
Contact: Prof. Rene Medema
E-mail: r.h.medema@umcutrecht.nl
Website: http://www.umcutrecht.nl/subsite/oncology/Research-groups/Medema/

General research focus: Cell cycle checkpoints and cancer

During mitosis, chromosome segregation occurs with extraordinary precision so that daughter cells end up with an identical set of chromosomes. This irreversible event represents the most vulnerable process during cell division. In fact, flaws in the mitotic checkpoints that monitor the fidelity of chromosome segregation lead to chromosomal instability (CIN), a defect common to most human tumours. CIN promotes tumorigenesis, but may also be the ultimate Achilles' heel of cancer, since the error-prone mitotic checkpoints can be utilized to selectively kill tumour cells.
To evaluate this possibility, it is essential that we understand the mechanisms that guard chromosomal segregation, and their defects in human cancer.

Fidelity of chromosome segregation is maintained by the spindle checkpoint. Yeast genetics have identified many components of this checkpoint, but the way it signals in time and space, its complexity in human cells, and its exact role in cancer are far from resolved. We want to clarify the molecular wiring of the spindle checkpoint in human cells through a combination of genetics and molecular cell biology.
We have developed RNAi-based methodologies allowing selective reconstitution experiments in human cells that were previously only feasible in lower eukaryotes.
Combined with our recently established assays to monitor spindle checkpoint surveillance and mitotic progression (i.e. time-lapse microscopy, FACS-analysis, kinase assays, APC-dependent protein degradation in live cells), this puts us in a unique position to elucidate the molecular details of this checkpoint in human cells.
Simultaneously, as spindle checkpoint surveillance is critically involved in CIN, it allows us to study the contribution of CIN to tumorigenesis and analyze the impact of spindle checkpoint malfunction on cytotoxicity of spindle poisons used in the treatment of cancer.

These studies will make a significant contribution to our understanding of how this intriguing checkpoint functions, which role it plays in the formation of cancer, and how we can utilize it for cancer intervention.

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