Every year, about 180 children in the Netherlands are diagnosed with a brain tumor. This concerns approximately 20 children medulloblastoom, a fast-growing tumor in the cerebellum. The chance of cure varies: it depends on the subtype and any metastases. One in four children suffers from long-term memory loss and speech problems after surgery. It is therefore very important to find new treatments with fewer side effects.
Micro-proteins
Microproteins are made from parts of DNA that were not previously known to be able to make protein. The Van Heesch group is investigating the role these small proteins play in the origin, development and treatment of childhood cancer. Micro-proteins remained hidden for a long time, partly because they were too small to be properly mapped. In new research, published today in trade journal Molecular Cellthe researchers shed new light on the role of microproteins for medulloblastoma.
Damon Hofman, PhD student in the Van Heesch group and co-first author: ‘For the first time, we have mapped and studied essential microproteins in medulloblastoma. This was possible thanks to new, more refined techniques. We could now demonstrate which micro-proteins and mechanisms are essential for the survival of a cancer cell.’
Dr. John Prensner, M.D.assistant professor of Pediatrics and Biological Chemistry at Michigan Medicine, and one of the study’s lead authors, said: “This research is critical to helping us understand how medulloblastoma works at the genetic and cellular levels so that patients can be appropriately treated and we can develop new therapies.’
Upstream open reading frames
To determine which microproteins are essential for medulloblastoma, the researchers studied so-called ‘upstream open reading frames’. Hofman explains: ‘Microproteins and normal proteins are made from exactly the same piece of genetic material, but originate from different parts of that molecule. One of the parts that plays a role in the production of micro-proteins is called ‘upstream ORFs’. Until now, these uORFs have been relatively underexposed, especially in childhood cancers and specifically medulloblastoma.’
To find out which protein – normal, micro or both – the cancer cell needs most, the researchers ‘cut’ the upstream ORF part from the cell using CRISPR technology. They saw a clear effect. Without the microproteins, the medulloblastoma cancer cells could not survive. The known proteins could be disabled without having an effect on the cancer cell.
Other forms of childhood cancer
Dr. Sebastiaan van Heesch, research group leader and junior Oncode researcher, calls the results promising: ‘The results from this study show the potential of this young research field. They confirm the crucial role of certain essential microproteins in the onset and development of medulloblastoma. Further research is now needed to determine how these microproteins can be used as targets for cancer-specific immunotherapy, and to explore their potential for therapy. This is a major motivation for us for further research in which we also map the essential micro-proteins for other forms of childhood cancer.’
2024-01-03 16:00:00
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