Bas van Steensel and Daniel Peeper (both NKI) and Alexander van Oudenaarden (Hubrecht Institute) receive 2.5 million euros as part of the ERC Advanced Grant. Van Steensel will use the grant to explore our messy genome, Peeper will focus on reinvigorating anticancer T cells, and Van Oudenaarden's project focuses on measuring protein production in individual cells.

We spoke with Bas van Steensel and Daniel Peeper about their projects, more information about Alexander van Oudenaarden's research can be found on the website of the Hubrecht Institute.

Why is our genome so messy?

“Our genome is a mess, we want to find out why.” That’s the basic question Oncode Investigator Bas van Steensel proposes to answer in the coming years. “With this ERC Advanced Grant we are going to find out why our genome looks so messy. Why are regulatory elements - the pieces of DNA that control the activity of genes - often at random distances from the gene they control? It all seems random, sometimes enhancers are before the gene they control, but we also find them after, in the middle, or very far away from a gene. What would happen if we placed it somewhere else, would they work less well in terms of regulating their target gene?”- says Oncode Investigator Bas van Steensel.

It is thought that the human genome harbours hundreds of thousands of enhancers and enhancer-like elements that together govern and modulate gene expression patterns in response to a myriad of signals. A remarkable feature is that these are found almost anywhere inside the gene they regulate and can act over enormous distances. Some enhancers control multiple promotors whereas other only activate a single promotor and leave other promotors unaffected. Some enhancers skip one or several promotors to selectively activate a more distant one. But what is the logic of this seemingly random arrangements? An answer to this fundamental question requires an experimental approach that is conceptually simple, but technically challenging.

Developing and applying a powerful hopping method

Bas van Steensel and his research team proposed an approach called “RE_LOCATE” and today received the news that the European Research Council awarded this with an ERC Advanced Grant. The aim of his research project is to develop and apply a powerful hopping method that allows pieces of DNA to easily move around the gene and to monitor the effects of gene regulation in this region. The ERC Advanced Grant awarded consists of nearly 2.5 million euro for 5 years.

The Bas van Steensel lab has studied gene regulation and chromatin architecture for more than 20 years by means of innovative genomics approaches. This technique will be applied in combination with other genomics approaches to carefully and systematically dissect the linear ordering of regulatory elements and how the position of a regulatory element influences its functionality. Not only will this work shed more light on basic questions which are still unanswered, it can also further our understanding of cancer. The obtained insights may help to understand what goes wrong in cancers where the genome is 'scrambled' and in this way open up new treatment avenues.

Studying specific T cells’ inability to eradicate the cancer

Oncode Investigator Daniel Peeper will use the ERC Research grant to investigate dysfunction of anticancer T cells. “Immunotherapy was a clinical break-through a few years ago, providing better perspectives for a growing number of cancer patients. Working on resistance to cancer precision medicines I was excited to witness this development, but I also considered the possibility that immunotherapy would soon be facing similar resistance challenges. Indeed, we know now that in spite of spectacular clinical responses seen in some patients, most fail to respond to immunotherapy because of resistance. Several causes underlie this problem, including the inability of specific T cells to eradicate the cancer. This ERC Advanced grant offers an excellent opportunity to study this problem and find answers that can be clinically translated to achieve more, and more durable, responses for patients” - says Oncode Investigator Daniel Peeper (NKI).

Some six years ago, Peeper refocused his laboratory from studying resistance to cancer medicines to immunotherapy resistance. Indeed, also for this type of treatment, serving to boost the patient’s own immune system, resistance is a formidable problem. It can occur right at the beginning of the therapy, but also later, after a period of good clinical response. The problems can originate in the cancer cells (by ducking the immune radar), but also in the immune system. For example, although antitumor T cells correctly localize to the cancer, they present themselves often in a dysfunctional state. As a result, they display only little antitumor activity. A key development was the introduction of so-called immune checkpoint blockade, which can re-activate such inactive immune cells. However, T cells can get dysfunctional in many other ways.

The genes that are responsible for T cell dysfunction

Today, Peeper received the news that the European Research Council has awarded his proposal entitled “ReverT” with a subsidy of 2,5 million Euro. His team will set out to identify the genes that are responsible for T cell dysfunction. For this, they will use advanced techniques to functionally interrogate the entire genome for factors that cause T cells to be inactive. But they will not stop there. The ultimate goal is to discover ways in which the corresponding proteins can be inhibited by new medicines, to revert T cell dysfunction so that they can eliminate the cancer more effectively.

Peeper: “With similar approaches, we have already identified several genes in cancer cells, whose inhibition makes them more sensitive to T cells. In the current study, we will focus our attention on the other side, and search for T cell genes, inactivation of which boosts their anticancer activity. Our preliminary results suggest that several such genes exist, so we are very excited to receive this major financial support to pursue this strategy”.

Read more on the website of the European Research Council.