Dutch Cancer Society (KWF) grant for Francesca Mattiroli

In the nuclei of our cells, 2 meters of DNA must be carefully packaged for storage and protection. The most compact packaging form is called heterochromatin, in contrast to the much looser euchromatin. Apart from protecting the DNA, this packaging also decides which genes on the DNA are turned on and off. DNA packaged tightly in heterochromatin is silenced, which means that the genes are inactive. This is about 40% of our DNA. The way the DNA is packaged therefore has an enormous influence on the behavior of the cell.

Careful replication

Every time a cell divides – billions of times per day in our body – this packaging organization needs to be carefully copied. A few hundred proteins are involved in doing this. If heterochromatin is not properly copied, DNA regions that are supposed to stay silent become active. This leads to abnormal behavior of the cell. Interestingly, scientists have observed that cancer cells often contain abnormal amounts of the proteins responsible for copying heterochromatin.

Understanding heterochromatin to fight cancer

With the KWF grant, Mattiroli, Janssen and Taneja aim to elucidate the link between aberrant replication of heterochromatin and the development of cancer. They want to study how the proteins that copy heterochromatin work, and compare this under normal conditions and in cancer, to reveal the weak points that can be targeted in cancer cells specifically. “This grant allows us to move closer to clinically relevant research,” Mattiroli says. “My group is focused on answering fundamental questions in biology, but with this grant, we can now take a step closer to using this fundamental knowledge to fight cancer.”

Cells and proteins in the lab

The team will use cultured human cells to determine which proteins bind to heterochromatin and how these proteins are involved in copying this compact structure. To study the proteins in more detail, The Mattiroli group will purify them and determine in a test tube how the proteins bind to each other and affect each other’s function. To simulate the changes seen in cancer, they will adjust the cultured cells to make them produce abnormal amounts of these proteins, and also use cancer cell lines. This allows them to see what happens to cells when heterochromatin replication is disrupted.

Laying the foundations together

This collaborative work will give more insights into the fundamentals of heterochromatin replication and stability. “I am excited to work in a team with Aniek Janssen and Nitika Taneja,” Mattiroli says. “We are putting our complementary expertise together to solve some long-standing open questions on heterochromatin stability. We would not be able to answer these with independent efforts, as together we can be more comprehensive and tackle the research questions from multiple angles, bringing in vitro biochemistry, cell biology and microscopy together, and providing stronger support for our scientific findings.”

Together, they hope to elucidate the link between heterochromatin defects and the development of cancer. Testing existing cancer medication on cells with specifically these defects, might give clues for developing new personalized treatments. The involvement of two university hospitals will help to bring clinically relevant results closer to the clinic.

About this KWF grant

This funding round, KWF is investing over 32 million euros in 51 research projects. The focus of these projects ranges from gaining fundamental insights into cancer development, growth and spread, to finding new biomarkers and drugs, to improving psychosocial care for cancer patients. Mattiroli’s project is one of the 21 fundamental research projects and is funded by the proceeds of Alpe d’HuZes. More information about the funded projects can be found on the website of KWF (only in Dutch).