
In the picture: Prof Dr Matthias Selbach,
Photo: Pablo Castagnola
Research success through first comprehensive study of the genome and proteome
Berlin, 28 June 2024
Multiple myeloma is one of the most common cancers of the immune cells of the bone marrow. It is still considered incurable today. Even if a therapy is initially effective, the cancer returns. Researchers at Charité – Universitätsmedizin Berlin, the Berlin Institute of Health at Charité (BIH) and the Max Delbrück Center, together with other partners, have conducted a comprehensive molecular study of the disease in order to be able to intervene more quickly and in a more targeted manner. The team has now described in the journal Nature Cancer* how particularly aggressive tumour variants can be detected at an early stage. It shows how changes in the genetic material affect the protein profile of the tumour cells and thus the disease mechanisms.
Multiple myeloma is a cancer in which immune cells of the bone marrow, known as plasma cells, degenerate. Plasma cells are responsible for the production of antibodies. Every person has a large number of different plasma cells that produce different antibodies in large numbers. This enables the body to recognise and fight various pathogens. In the case of multiple myeloma, a single plasma cell develops into a tumour cell. It multiplies unchecked and forms a monoclonal cell population, i.e. many cells are created that are all exactly the same and initially genetically identical. They also often produce large numbers of antibodies or fragments of them – but these are non-functional.
In the course of the disease, several tumour foci usually develop in many places in the bone marrow, hence the name: multiple myeloma. Immunodeficiency, kidney failure, bone loss and fractures are just some of the consequences of uncontrolled cell growth. Despite therapeutic advances and the introduction of new cellular immunotherapies, there is still no cure for multiple myeloma. A research team led by Prof. Jan Krönke, Medical Clinic with a focus on haematology, oncology and tumour immunology at Charité, and Dr Philipp Mertins, Head of the Proteomics Technology Platform at the Max Delbrück Center and BIH, has therefore set out in search of new diagnostic and therapeutic approaches.
Which path does the tumour take?
Every cancer is different, as is the case with multiple myeloma. Tumour foci develop individually and at different speeds. This makes it difficult to assess the course of the disease and choose the optimal treatment. While altered plasma cells sometimes spread only slightly, in other cases they behave extremely aggressively, which is associated with a poor outlook for the further course of the disease.
So what makes the progression of multiple myeloma so different? Together with experts in protein analysis from the Max Delbrück Center and the BIH, the researchers examined genetic and molecular changes in the tumour cells in detail in a group of more than one hundred patients. Data from patients of the German Multiple Myeloma Study Group (DSMM), which is coordinated at the University Hospital of Würzburg, was included. The researchers were thus able to include clinical data from patients treated uniformly over a period of eight years and longer after initial diagnosis.
Systems medicine and very large amounts of data
While the changes in the genome and their effects on the proteome have already been well described for other types of cancer, this is the first comprehensive proteogenomic study for multiple myeloma. “Genetic data alone is not enough to elucidate the disease mechanisms,” says Dr Mertins. “We wanted to know what consequences genetic changes have at the protein level and compare these molecular biological data with the actual course of the disease in patients.” The team was supported by experts from Charité, BIH and the German Consortium for Translational Cancer Research (DKTK) in collecting and analysing the extensive amounts of data.
The latest mass spectrometry methods made it possible to create the protein profile of degenerated plasma cells and compare it with the profile of healthy plasma cells from people without the disease. The result: both genetic changes and changes in the signalling pathways lead to uncontrolled activation of the cancer cells. Regulatory processes at the protein level had the stronger influence. The researchers were able to identify a protein constellation that indicates a particularly aggressive course of the disease, regardless of known risk factors.
Systems medicine and very large amounts of data
While the changes in the genome and their effects on the proteome have already been well described for other types of cancer, this is the first comprehensive proteogenomic study for multiple myeloma. “Genetic data alone is not enough to elucidate the disease mechanisms,” says Dr Mertins. “We wanted to know what consequences genetic changes have at the protein level and compare these molecular biological data with the actual course of the disease in patients.” The team was supported by experts from Charité, BIH and the German Consortium for Translational Cancer Research (DKTK) in collecting and analysing the extensive amounts of data.
The latest mass spectrometry methods made it possible to create the protein profile of degenerated plasma cells and compare it with the profile of healthy plasma cells from people without the disease. The result: both genetic changes and changes in the signalling pathways lead to uncontrolled activation of the cancer cells. Regulatory processes at the protein level had the stronger influence. The researchers were able to identify a protein constellation that indicates a particularly aggressive course of the disease, regardless of known risk factors.
Towards new therapies
“The findings will help to better classify patients into subgroups in future and thus personalise treatment,” concludes Prof. Krönke. “We have identified important proteins and signalling pathways that could form the basis for even more effective and tolerable therapies for multiple myeloma, for example for immunotherapies such as CAR T-cell therapy.” In further steps, the scientists will investigate which of the target structures identified are actually suitable for new therapeutic approaches.
The study is a key resource for research and application-related development, emphasises Dr Evelyn Ramberger, first author of the study: “To make the complex data set manageable, we have programmed an interactive and freely available online tool.” This gives cancer researchers easy access to the results and allows them to use the information to develop new therapies and tests to guide treatment. For example, patients with a particularly aggressive form of multiple myeloma could potentially be treated with a more intensive therapy right from the start.
*Ramberger E et al. The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities. Nature Cancer 2024 Jun 28. doi: 10.1038/s43018-024-00784-3
Mass spectrometry
Mass spectrometry is a technical method for analysing the mass of molecules and atoms. The substance to be analysed is ionised and transferred into a gas phase. The resulting ions are strongly accelerated using an electric field and sorted in the analysing unit of the mass spectrometer according to the ratio of their mass to their charge. The mass spectrum of a substance provides information about its molecular composition. Mass spectrometry is therefore suitable for identifying, characterising and quantifying a large number of biomolecules, such as proteins, metabolites, sugars and fats, which behave differently depending on the clinical picture and the individual.
About the study
The study was supported by the German Consortium for Translational Cancer Research (DKTK), the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), “Mass spectrometry in Systems Medicine” (MSCorSys), the Wilhelm Sander Foundation and the Berlin Cancer Society. In addition to researchers from Charité, the Berlin Institute of Health at Charité (BIH) and the Max Delbrück Center, experts from the German Cancer Research Centre (DKFZ) and the University Hospitals of Würzburg and Ulm, as well as the German Multiple Myeloma Study Group (DSMM, coordinated by Prof. Stefan Knop and Prof. Hermann Einsele), contributed significantly to the work.