Thymic cancer

Origin of a rare disease identified
 

November 09, 2022

The thymus is crucial immune organ for the defense against infectious diseases as well as cancer. In rare cases, a tumor can develop in the thymus, but little is known about the development of this rare form of cancer. At the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, researchers have now developed the first animal model to track down the origin of this unique form of tumour. The results show that the tumour arises from cells whose maturation is blocked by a specific type of genetic alteration, ultimately resulting in a weakened immune defense. The project was supported by the Wilhelm Sander Foundation and recently published in Communications Biology.

The thymus is located in the thorax and is essential for our immune defense. In this organ, various types of T cells mature, including the famous killer T cells, which can specifically destroy virus-infected and malignant cells, and so-called T helper cells, which support antibody-producing B cells in their fight against foreign substances. During the first years of life, the thymus is most active, since the body’s immune system must be quickly and reliably supplied with sufficient numbers of T cells. After fulfilling this essential task, the thymus shrinks, although, even in advanced age, the thymus does not disappear completely. In rare cases, malignant transformation of the thymic tissue occurs. The majority of these tumors grow slowly, but nonetheless require rapid treatment to save the patient’s life. To this day, surgical removal is the mainstay of therapy. The hope is that a better understanding of the origin and characteristics of thymic tumours may enable the development of targeted therapies.

Effects of a mutated gene switch identified

Researchers led by Prof. Thomas Boehm at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg have resorted to a well-established and successful approach of animal models in cancer research to study the characteristics of different types of cancer and to test novel forms of therapy. Their starting point was the discovery of a genetic alteration in a gene that is often associated with thymic tumours and acts as a switch to activate numerous other genes. However, it had remained unclear how a single mutation in the gene called GTF2I causes tumour development. To answer this question, the researchers used the molecular trick to introduce the mutation into the genome of mice. Then they compared the activity of the mutant regulator protein to its normal counterpart to track down the changes developing in the diseased thymus.

This discovery represents a significant advance in two respects. On the one hand, the team in Freiburg was able to identify a previously unknown intermediate step in the development of the stroma in the thymus, advancing the knowledge about this crucial but still largely enigmatic cell type. And on the other hand, they could show that the intermediate stage thus identified marks a particularly susceptible point in the life of stromal cells where they are easily transformed into malignant tissue. In addition, the new animal model will enable the search for drugs that may break this blockage and thus normalize the formation of the stroma again.

“Our study shows yet again how important animal experiments can be for progress in understanding the biology of human tumours. This is particularly true for rare diseases such as thymic cancer, which often receive only little attention,” says Thomas Boehm.

The researchers now aim at refining their animal model to make it even more similar to the situation found in patients. In particular, they hope that a precise understanding of the gradual development of the tumours will enable them to develop a stage-related therapeutic regimen that could allow risk-adapted treatment of the affected patients.

 

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