The more damage is accumulated in the DNA of a cell, the more likely it is to spin out of control and cause cancer. But for Oncode Investigator Sylvie Noordermeer (LUMC), that genetic damage also opens a therapeutical window. She imitates cancer cells in the lab by inflicting DNA damage, finding new targets for more effective treatments.
Sylvie Noordermeer - Group leader at Leiden University Medical Center and Junior Oncode Investigator
Breaking new ground
One of the most important genes in tumor formation is BRCA1. ‘Even after 30 years, its precise function remains unknown’, says Sylvie Noordermeer. ‘We know that the gene is responsible for the repair of DNA double-strand breaks and that a cell with a damaged BRCA1 gene repairs less of its DNA damage. So, a mutation in BRCA1 is more likely to cause cancer. However, it’s not limited to hereditary forms of breast cancer – about five percent of all tumors possess a BRCA1 mutation. That’s a lot.’
Sylvie Noordermeer started her scientific career at the Radboud Institute for Molecular Life Sciences in Nijmegen, where she studied chemistry and obtained her Ph.D. in the fields of hematology and molecular biology. In that period, she worked on the modification of proteins after the translation from RNA to protein and the role of these modifications in DNA damage. After that, Noordermeer focused on BRCA1 during a postdoc at the Lunenfeld Tanenbaum Research Institute in Toronto, Canada. ‘Novel medicines, like PARP inhibitors, push cells with a BRCA1 deficiency towards producing even more DNA damage, leading to cell death. But these drugs may also lead to secondary mutations in the tumor DNA and therapy resistance.’
Once back in The Netherlands, Noordermeer’s knowledge in the field of DNA damage and BRCA1 proved to be fertile ground for further research. Still focusing on BRCA1 deficiencies and secondary mutations, she and her colleagues now try a mechanistic approach to uncover the process behind the repair of double-strand breaks, one of the most toxic types of damage to the DNA.
In the last two years since Noordermeer became an Oncode Investigator, she started to believe that different mutations in the BRCA1 gene lead to different effects in formation of BRCA1-associated protein complexes. ‘We know that mutations in BRCA1 are not limited to hotspots, and the protein is inclined to form complexes with other proteins’, she says. ‘Our research could help us understand how these complexes form, why mutations lead to tumor growth in different forms, and why tumors with the one mutation don’t respond to a therapy or cause a more aggressive clinical picture, in contrast to the other.’
That multiformity is also expressed in the means cells possess to repair their DNA damage. ‘How a cell chooses a repair mechanism, we don’t know’, Noordermeer says. ‘But while all repair mechanisms fix the DNA to some extent, they are not equally efficient or accurate.’ Therefore - to study the mechanism behind the repair of double-strand breaks, Noordermeer induces the damage herself. That could shed light on the effects of DNA damage and reparation, and the cellular elements that determine the choices of repair.
"I like to do mechanistic cancer research, but in the end, it’s the patient that counts"
‘Essentially, we cut the DNA, just like when a strand breaks’, Noordermeer says. ‘We used to do that with radiation or medicines, but those methods left us uncertain as to where the damage would occur.’ By using the novel molecular cut-and-paste technique CRISPR-Cas9, she knows exactly where the break in the DNA strand occurs. The technology is based on two components – a gRNA, being a short piece of RNA that forms the address label to the correct location in the DNA, and Cas9, a pair of molecular scissors. The combination allows for a perfectly aimed break in the DNA, making the process easier to follow. Noordermeer also uses CRISPR-Cas9 to build cell lines with a mutated or nonfunctional version of BRCA1. ‘It enables us to genetically imitate a tumor. That’s better than all the models we have used in the past.’
In the field of DNA damage research, CRISPR-Cas9 became the cornerstone of molecular biology in just a few years. ‘It shook up our field, in a good way’, Noordermeer says. ‘All CRISPR-Cas9 does is break double-stranded DNA, insert new DNA, and repair it. That greatly expanded the toolbox of molecular biologists, but it helped our specialism of DNA damage research in particular.’ The fact that the two inventors of CRISPR-Cas9, Jennifer Doudna and Emmanuelle Charpentier, were awarded the latest Nobel Prize for Chemistry, only advanced that. ‘I can notice there is more interest in our research, and what it means for cancer patients. It’s great to be able to talk to people outside our field about the methods we use.’
Catalyzed by the recent interest in CRISPR-Cas9 and its applications, Noordermeer’s research starts to gain momentum. ‘We’re still a young lab,’ she says, ‘but collaborations are forming already. We share our tools and methods with other labs, and they return the favor by helping us out. Also, we’re stationed in the LUMC, where there are lots of data on BRCA1 tumors, and expertise of clinicians in the field of hereditary breast and ovarium cancer.’ That translational research is an important motive for Noordermeer. ‘I like to do mechanistic cancer research, but in the end, it’s the patient that counts.’
As a starting investigator with a research group of five, Noordermeer is glad to be part of Oncode. ‘With a project grant, it’s hard to try something if you’re not sure it will work. A baseline grant allows me to think creatively and out of the box.’ What’s more, Oncode helps her develop the skills necessary as a group leader by offering collaborations with other researchers. ‘I instantly was part of a network which would have taken years to build up.’ It feels like a community, she says, where the focus is on cooperation, instead of competition. ‘For me, as a young group leader, it helps me to get a strong foothold. At the same time, I can learn from other groups or hotshots in the field. In a strongly competitive scientific world, that’s a refreshing idea.’
Credits: interview by Koen Scheerders; photography by Marloes Verweij, Laloes Fotografie