Four studies can get started thanks to KWF Dutch Cancer Society

Four research teams at the Netherlands Cancer Institute can get started after getting the green light from funder KWF Dutch Cancer Society. How much chemotherapy actually reaches the cancer cells? And how do they keep their DNA stable enough to stay alive? The researchers will tackle these unanswered questions, and more.

Breaks on instability
How do cancer cells keep their genomes, their genetic material, stable? Although changes to the genome can be a driving factor in cancer growth, too much genomic instability can be deadly, also for cancer cells. That's why aggressive tumors develop ways to limit this instability. "We know very little about how they do this, which means that we lack fundamental knowledge about cancer that could possibly give us new leads for new therapies," says group leader Jacqueline Jacobs. She wants to use her new KWF grant to tackle this. "Building on our recent findings around the protein KAP1, we will investigate how cancer cells counter instability."

Mild mutations
Group leader Titia Sixma will use her new grant to delve into the ingenious system of DNA mismatch repair (MMR). This repair system is essential for the maintenance of DNA and, as a result, health. If certain aspects don't work due to, for example, a mutation, the risks of developing colorectal cancer and uterine cancer (Lynch Syndrome) are increased. Some mutations in MMR genes only have a limited effect on the repair system. "These mild mutations can have a special effect on the repair," says Titia. "In our new research, we will study how these mild variants affect the repair mechanism. This could be important in screening and treatment of patients with Lynch Syndrome and such mutations."

Reached your destination?
Postdoc Bram Thijssen will look for a way to measure how much chemotherapy will eventually reach the cancer cells. He will specifically look at the chemotherapy medication carboplatin, a very effective treatment for ovarian cancer. Unfortunately, in most patients the medication does not eliminate all cancer cells. How these cells manage to escape is not clear. Bram: "In this new study, we will look at thousands of individual cells from metastases, to closely investigate how much carboplatin reaches the cells, and how they respond. We hope to develop a method that can determine whether sufficient medication reaches its destination, which can hopefully help us explain why certain cells are not eliminated."

Deciphering crosstalk
Another important question scientists grapple with, is: why do some cancer patients respond to immunotherapy very well and others do not? In this context, the new KWF grant allows group leader Daniela Thommen to investigate what is happening in the complex crosstalk between all kinds of cells in the tumor environment. Daniela: "Tumors are complex ecosystems in which cancer cells, immune cells and stromal cells 'speak' with each other via secreted signaling molecules. This dynamic crosstalk can boost or limit the function of immune cells and their response to therapy. Using patient-derived tumor models (tumor avatars) we will map secreted mediator patterns across hundreds of tumors. Then, we aim to identify tumor, immune and tissue features that shape this activity, and that could be therapeutically targeted to develop more personalized immunotherapies".

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