Medema group

Group leader: Prof. dr. René Medema

‘Causes and consequences of extrachromosomal DNA in pediatric cancer’

The activation of oncogenes is a defining feature of cancer. In several cancer types, among them several childhood cancers, activation of these tumor-driving oncogenes occurs via amplification on extrachromosomal DNA (ecDNA). We are interested in the causes as well as consequences of ecDNAs: how are these DNAs formed, what factors are needed to maintain ecDNAs, and are there specific vulnerabilities associated with ecDNA presence?

'To understand, at a mechanistic level, how genome maintenance pathways ensure faithful cell division, while also revealing the causes and consequences of disturbed genome control in cancer’ Prof. dr. René Medema - Group leader

‘Functional genetics of DNA repair pathways’

A mainstay of chemotherapeutic anti-cancer regimens is the use of DNA damaging agents (i.e., cytostatics). These drugs are frequently used to treat several childhood cancers. In response to DNA damage, cells activate sophisticated DNA damage repair pathways that can repair inflicted damage. Through the use of genome-wide genetic screening in combination with state-of-the-art cellular and molecular biology, we aim to obtain detailed mechanistic insight into DNA damage detection and repair pathways. By doing so, we endavour to generate comprehensive genetic networks centred on DNA repair mechanisms, which we envision can help us predict and potentially improve the efficacy of DNA damaging cytostatic treatments in childhood cancers.

‘Germ line genes, genome maintenance and cancer’

The germ line is responsible for the production of highly specialized reproductive cells – sperm and egg – that enable sexual reproduction. The generation of these unique cells requires radical adaptations to the cell division program that normally enables proliferation of non-germ cells. These adaptations are driven by the action of hundreds of germ cell-specific proteins. Expression of these germ cell genes is normally – as to be expected – restricted to cells in the germ line, but many cancers aberrantly re-express a selection of these germ cell-specific factors. The genes that exhibit this behavior are collectively referred to as ‘Cancer Testis antigens (CTAs) or Germ Cell Cancer Genes (GCCGs)’. We are interested in studying these genes in cancer, in order to understand:

• how they contribute to pathological behavior in (pediatric) cancer; and to
• reveal if their aberrant presence creates specific cellular vulnerabilities that can be exploited through specific therapeutic strategies.

We are currently focusing our attention on a selected group of CTAs/GCCGs that specifically influence maintenance pathways that are crucial for genome control, and aim to expand our research with a specific focus on genes that show aberrant re-activation in childhood cancers.