"I have been intrigued by how one single factor could elicit so many different biological effects ever since I was a master’s student", says Oncode Investigator Peter ten Dijke. He means the TGF-β growth factor, to which he eventually devoted his entire career.
Peter ten Dijke
Professor of molecular cell biology at Leiden University Medical Center.
The fine art of interfering without causing side effects
Ten Dijke is a professor of molecular cell biology at Leiden University Medical Center. His face is beaming as he speaks about his favourite protein: “TGF-β – which is short for transforming growth factor beta – is a multifunctional regulator that is produced by many different cell types. It mediates tissue invasion and metastasis of cancer cells, tumour vascularization, immune suppression, and therapy resistance. I want to understand how this works, with the idea that if I can understand it, I can probably manipulate it and use it to develop novel cancer treatments.”
But interfering with TGF-β signalling is not straightforward because the protein plays a key role in normal cell growth and function as well. It can even act as a tumour suppressor. Manipulating it would likely cause serious side effects. Ten Dijke’s research group have set themselves the goal to discover ways to selectively interfere with the cancer-promoting effects of TGF-β, while leaving its tumour suppressive effects intact. They are combining detailed insights into the biology of the TGF-β pathway with the latest chemical technologies to manipulate specific elements of the dynamic signalling processes.
"I want to understand how things work, with the idea that if I can understand it, I can probably manipulate it and use it to develop novel cancer treatments."
“We recently switched to the approach of combining biology and chemistry. Funding from Oncode Institute has enabled us to gather preliminary data to demonstrate the power of this approach. This is important because preliminary data are required to attract additional research funding. There is also a strong chemistry group within Oncode: the group of Huib Ovaa. Unfortunately, Huib passed away last year, but we still have strong contacts with the members of his group. We are jointly synthesizing new compounds to target enzymes that regulate the TGF-β pathway”, explains ten Dijke.
“In addition, we are using fluorescent activity-based probes to investigate the dynamics of the signalling pathway. I think this dynamic aspect is critical. Perturbations that are associated with cancer will not be present continuously. Rather, they are a dynamic response. Probes allow us to gain detailed insights into dynamic processes in cells, and even in complete organisms such as zebrafish and mice. We are particularly interested in so-called ‘deubiquinating enzymes’, which control the stability of signalling molecules. By inhibiting these enzymes, we can render the TGF-β receptor less stable and make the TGF-β pathway less active. People were sceptical about this approach at first. However, the first molecules that selectively target these enzymes have now been generated and they seem to have quite potent activity. We will investigate if it is possible to use these molecules as drugs to treat cancer with fewer side effects.”
Long non-coding RNAs
Chuannan Fan, a talented PhD student in ten Dijke’s lab, provides another example of the group’s approach. He joined ten Dijke’s research group three years ago to study the role of long non-coding RNAs (lncRNA) in TGF-β signalling and breast cancer progression. “Only 2% of the human genome represents protein coding genes. Parts of the remaining 98% are transcribed into so-called ‘long non-coding RNAs’. These are strands of more than two hundred nucleotides that are not translated into proteins, but act as key regulators in various cell processes. We study the behaviour of these molecules in cell cultures, tissue cultures, and zebrafish models, and we use advanced technologies to modify their expression. This provides insight into how these lncRNAs modulate the TGF-β signalling pathway. Interestingly, specific lncRNAs appear to be only active in certain cells. This creates opportunities to specifically target the TGF-β pathway in certain cells and avoid effects on other cells” he explains.
The team seems to be on to something: “We have identified two novel lncRNAs that regulate specific elements of TGF-β signalling and cell migration. One is a tumour suppressor that is downregulated in lung cancer patient samples compared to normal control tissues. In addition, the level of this lncRNA is positively correlated with patient survival probabilities in breast and lung cancer. We are planning to collaborate with a research group in Utrecht to deliver this molecule into cancer cells and investigate if it inhibits tumour growth, first in cell cultures and then in mouse models. The other lncRNA seems to promote TGF-β signalling and cancer progression. We would like to use a novel method called RIBOTACs to inhibit this molecule in cells” adds Fan.
The RIBOTACs technology was developed by the lab of Matthew Disney in the USA. “Oncode’s Business Development Team has brought us into contact with him”says ten Dijke. “This is an exciting emerging technology that utilizes so-called bifunctional molecules. One part of the molecule can bind to an RNA and the other part will recruit ribonucleases, thereby selectively targeting this specific RNA for degradation. Small molecules are relatively easy to deliver to patients, rendering them promising drug candidates. This technology could be applied in any type of cancer, but also in genetic diseases. We are keen to explore this” he adds.
Although Professor ten Dijke’s daily work takes place in the world of molecules, he certainly does not lose sight of the world of patients. Ten Dijke is among the first Oncode Investigators to enrol in Oncode’s Patient Engagement Programme, which aims to bring researchers and patients together. “I think we started about one and half years ago. I have been in contact with three patients now. They visited our lab and we had very inspiring conversations. They were interested to learn how we conduct our fundamental scientific research. They also had many practical questions, for instance if certain dietary adjustments may have beneficial effects on their health, or why it is necessary to have so many rounds of chemotherapy” he explains.
“I found it highly motivating to learn about the perspectives of these patients. The story of some of them is truly heart breaking; they have been on a rollercoaster with many treatments. These stories give me the energy to continue in times when all laboratory experiments seem to fail. They also provide novel perspectives. For instance, I learned that it may be very painful for patients to have a biopsy taken. I did not truly realize this when using biopsy materials in the lab. It makes me treat the samples with even more respect than before. Another big advantage of the Patient Engagement Programme is that some patients are very active patient advocates with large networks. They can accelerate research by bringing researchers into contact with clinicians and patient organizations” he adds.
Closing the circle
Ten Dijke turned sixty last year. “This made me realize that I have only limited time left in my career. So, I really have to focus now”. His ambition is to bring their latest discoveries to patients. “Oncode is very strong in valorization of basic research; we receive a lot of support in this. I started my career at a company and I would really like to end it by bringing a new treatment to the market. That would close the circle” he concludes.
Credits: interview by Linda van den Berg; photography by Marloes Verweij, Laloes Fotografie