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Emerging 'from nowhere': microproteins offer new leads for cancer research

Tiny proteins play an unexpectedly important role in the human body and diseases such as cancer. The presence of thousands of micro-proteins in human organs was previously demonstrated by researchers at the Princess Máxima Center in Utrecht and the Max Delbrück Center in Berlin. In a new study, the international team describes that these microproteins originated in the human body not so long ago and that, despite their young age and small size, they can influence important processes in healthy and diseased cells. This offers numerous new leads for further research into the origin of diseases, including cancer.

Small substances in the body can have a big impact. Millions of hormones and other biomolecules roam around in our cells and tissues and play leading roles in many of the key processes in our bodies. Yet small micro-proteins were often missed or dismissed as less important.

Led by Dr. Sebastiaan van Heesch, research group leader at the Máxima Center, and Prof. Dr. Norbert Hübner of the Max Delbrück Center, researchers have further investigated the microproteins they previously discovered. They now show that these previously ignored microproteins may play a role in important processes in both healthy and cancer cells. The research, published today in Molecular Cell, also shows that these small molecules are a recent ‘invention’ during human evolution.

Evolutionarily interesting

The new, young group of microproteins is unique. Van Heesch: 'They originated 'out of nowhere,' in places in our DNA where previously there was no proper code for making a protein. Microproteins can still be found in some human-like monkeys, but not in other animals, such as mice, pigs, or fish.' The researchers concluded this from experiments and extensive analyses comparing DNA from more than 120 animal species. In these, they showed which pieces of DNA coded for the small proteins, and when changes in that genetic code had occurred that made this possible. 'That proteins can be ‘born’ this way, and thus are not always copies of older proteins, has not been known for a long time. This research reveals the scale at which this has happened in humans. It is possible that evolution is thus more dynamic than previously thought.'

To their surprise, the researchers saw that the much ‘younger’ microproteins can bind to older proteins. Binding is necessary to activate proteins. Dr. Jana Schulz, along with Dr. Clara Sandmann and Dr. Jorge Ruiz-Orera lead author of the paper: ‘Despite the huge age and size difference between the proteins, they appeared to 'talk' to each other.’ Hübner adds: 'Our experiments showed for the first time that the young and old proteins can bind to each other and thus potentially influence each other.' Dr. Clara Sandmann: 'Sometimes these proteins are even much smaller than we thought. However, we do not yet know exactly what most of these micro-proteins do in our bodies.'

New leads

In his research group at the Máxima Center, Van Heesch is looking at the role of microproteins in the development of childhood cancer. He explains: 'If you know which processes cause a tumor cell to grow, you can look for a treatment that acts on the cell and stops this growth. Microproteins are difficult to detect, but we have now found them in many different childhood cancers. In early embryonic development, when most childhood cancers arise, many of these evolutionarily young microproteins are actually made. Why that happens, we don't know. Because we have now seen that they bind to other proteins, it may be that this is how they influence development from fertilized egg to baby.' So far, microproteins have not been included in research on the development of childhood cancer. Van Heesch adds: ‘So with these thousands of proteins, we have found a large amount of new leads for further research into the processes that contribute to the development of childhood cancer.’

The international research team consists of scientists working at the Princess Máxima Center, the Max Delbrück Center, the Berlin Institute of Health (BIH) and the German Center for Cardiovascular Research (DZHK).