Chemists aim to disrupt cancer-related protein

How can we understand a protein when it is never still, but constantly changes shape? This is one of the challenges for LiU researchers who are studying the cancer-related protein MYC. The goal is to lay the foundation for the development of a cancer drug by showing in detail how this elusive protein works.

Alexandra Ahlner "This research is an exciting mix. It’s about understanding nature, at the same time as our methods involving lots of programming and data analysis with elements of quantum mechanics”, says Alexandra Ahlner, standing here in front of NMR equipment in the lab. “I think it is so fascinating, and completely mysterious, that the human body works as it does. The fact that it sometimes goes wrong is, I think, less strange than the fact that it so often works. In our research, we try to understand the processes that so often go wrong in cancer”, says Alexandra Ahlner, principal research engineer at the Department of Physics, Chemistry and Biology (IFM).

Cancer occurs when cells develop properties which lead them to “break rules”. Cancer cells can defend themselves against being killed by the body’s immune system, and can multiply unrestrained, spread to other places in the body and build new tumours there. They can even become unkillable. For this to happen, many of the cell’s functions must be disrupted in a way that helps transform it from a normal cell into a tumour cell.

Spurs on cancer cells

The researchers in Professor Maria Sunnerhagen’s group are interested in a protein by the name of MYC. MYC is second on the list of most commonly malfunctioning proteins in cancer (the protein p53 takes the none-too-flattering top spot on this list). MYC is often abnormally active in aggressive cancer cells, where it works as a kind of jammed accelerator that spurs on the development of tumours. Finding ways to slow down MYC would, therefore, be a way forward in the development of new drugs against cancer. Researchers around the world are searching after ways to do that. It is, of course, not as easy as it sounds.Alexandra Ahlner prepares an NMR-test."This research is an exciting mix. It’s about understanding nature, at the same time as our methods involving lots of programming and data analysis with elements of quantum mechanics”, says Alexandra Ahlner, standing here in front of NMR equipment in the lab.

“MYC is involved in lots of processes in healthy cells. You can't just shut it down completely, as that would lead to other things ceasing to work in the cells”, says Alexandra Ahlner.

In other words, fine adjustments are needed. And the researchers need to find several different ways of adjusting MYC activity in cancer cells. That which manifests as heightened MYC activity in tumours may be the end result of many different mechanisms. That which has gone wrong with it may be different from case to case.

“Our goal is to find a panel of molecules which can be used to stop the advance of MYC in the body. Our research is about opening up possibilities to attack MYC from one direction, but there are lots of other directions from which we can approach it too. We hope that in ten years’ time, we will have a sound method based on structural biology for stopping MYC”, says Maria Sunnerhagen.

Constantly in movement

For researchers in structural biology, who study the structures of proteins and their three-dimensional forms, MYC constitutes an exciting challenge. That is because it constantly changes shape.

In recent decades, researchers have ascertained the existence of so-called “intrinsically disordered” proteins. Around one third of all proteins contain “disordered” elements, which makes them very adaptable. MYC is one of these proteins.

“I think that by far the most interesting aspect of all this is not how the proteins look, but how they move. Instead of taking a static picture of them, we want to film them, you could say. But of course, the proteins are too small to be able to film them in the ordinary sense. So we need instead to find the parameters to describe them and then model this in the data”, says Alexandra Ahlner, who began her academic career with an MSc in chemical biology at LiU.Alexandra Ahlner and NMRThe NMR equipment with which the researchers examine proteins has its own room. The process can be disturbed by vibrations, so people with pacemakers are not allowed near the strong magnet.

So how can one understand the shape of a protein that is constantly moving? In this case, the researchers use nuclear magnetic resonance (NMR). This method is based on the fact that atom nuclei have magnetic properties which makes them work like tiny magnets. This is what lies behind the magnetic cameras which are used for medical examinations. But the NMR equipment which the researchers have in their lab subjects the samples to much stronger magnetic fields. Put simply, the researchers look at the signals that are changed when the chemical surroundings of the atom change. Such a change might, for example, take place when a protein folds in a new way that brings atoms closer together in the new, three-dimensional shape. Or when atoms in another protein end up close to one another as a result of both proteins interacting with each other at that specific point in time. By carrying out these NMR tests under various conditions, the researchers can draw conclusions about how proteins move around, or which parts of the protein are most important in interactions with other proteins.

This is because MYC doesn’t work alone. What MYC does in cells is affected by the fact that this protein interacts with more than 300 other proteins. Its adaptive ability is probably thanks to the fact that it is an intrinsically disordered protein which can change its structure lightning fast. One way of adjusting MYC activity in the cell might, therefore, be to interrupt the interaction between MYC and the proteins with which it interacts and cooperates.

Researchers have recently, in collaboration with Canadian colleagues, studied in detail the interaction between MYC and another protein – something which indirectly affects the levels of MYC in the cell.

“In most cases of cancer, the problem is that there is too much MYC. So we are interested in seeing if it is possible to reduce these levels. Previous studies have shown that if the interaction between these proteins can be hindered, MYC breaks down to a larger extent”, says Alexandra Ahlner.

In a study recently published in the journal Nucleic Acids Research, the researchers show which parts of both proteins are directly involved in this interaction. These areas comprise new, interesting targets for future drugs aimed at hindering the function of MYC in tumour cells.

Remote postdoc

The study is a result of a collaboration in which Alexandra Ahlner is a postdoc in a Canadian research group, while still living in Linköping.Maria Sunnerhagen and Alexandra Ahlner.Maria Sunnerhagen and Alexandra Ahlner.

“I think you have to be flexible about finding ways to do a postdoc. For example, doing one even if it hasn't been possible to move abroad for several years now”, says Maria Sunnerhagen.

The original plan was that Alexandra Ahlner would do part of her research in Linda Penn’s research group in Toronto. But after an initial visit to Toronto, the COVID-19 pandemic swept over the globe. During the pandemic, Alexandra has taken part in the Canadian researchers’ meetings via video link.

“The fact that Alexandra has had regular meetings with another research group is very positive. It has brought input into our research environment in a way which would not have been possible prior to the pandemic. It is extremely important to participate in scientific discussions in another research environment than that in which you have done your PhD”, says Maria Sunnerhagen.

This collaboration with the Canadian researchers has been in place for several years, but the researchers from LiU feel that the extent of the collaboration has deepened during the pandemic. Partly because it has become easier to communicate digitally. They plan to continue to have short video meetings. Maria Sunnerhagen believes that the pandemic has affected how people think about travelling, and that short transatlantic trips won’t be necessary in the future.

“When we do travel, we will be away for a few weeks. I also believe that the possibilities for researchers to collaborate digitally will affect how we run PhD programmes and the awarding of postdocs, if we play our cards right. It may allow us to award postdocs in other countries in a new way, which will make our research profile more agile. I think that is very positive.

Artikeln: The MYC oncoprotein directly interacts with its chromatin cofactor PNUTS to recruit PP1 phosphatase, Yong Wei, Cornelia Redel, Alexandra Ahlner, Alexander Lemak, Isak Johansson-Åkhe, Scott Houliston, Tristan M.G. Kenney, Aaliya Tamachi, Vivian Morad, Shili Duan, David W. Andrews, Björn Wallner, Maria Sunnerhagen, Cheryl H. Arrowsmith and Linda Z. Penn, Nucleic Acids Research Volume 50, Issue 6 3505-3522, published online 4 mars 2022, DOI: 10.1093/nar/gkac138

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