Scientists clarify the origin of a rare disease
The thymus is vital for defense against infectious diseases as well as cancer. In rare cases, a tumor can develop in an inconspicuous organ of the immune system, about the development of which little is known. Scientists at the Max Planck Institute for Immunobiology and Epigenetics in Freiburg have now developed the first animal model to trace the origins of thymus cancer. The results show that the tumor develops from cells whose maturation is blocked by certain genetic changes and thus weakens the immune system.
The thymus is an organ in the chest that is essential for the immune system. On the one hand, the so-called killer cells, which can destroy virus-infected and degenerated cells in a targeted manner, and on the other hand, helper cells, which provide B-cells producing antibodies with important help in the fight against foreign substances in the body, matured in it. In the first years of life, the thymus develops the most activity, because the body’s immune system must be quickly and reliably equipped with defense cells. Having fulfilled this vital task, the thymus shrinks, but does not completely disappear even with advanced age.
In rare cases, malignant degeneration of thymus tissue occurs. Although most of these tumors grow slowly, they require immediate treatment to save patients’ lives. Surgical removal is currently the mainstay of therapy, as the origin and characteristics of thymus tumors are not sufficiently known. Only knowledge of this enables the development of targeted therapies.
The effect of the mutated switch gene was detected
A proven and successful principle in cancer research is the use of animal models, on which the peculiarities of different types of cancer can be investigated and new forms of therapy can be tested. Scientists led by Thomas Boehm from the Max Planck Institute for Immunobiology and Epigenetics in Freiburg took this path. Their starting point was the discovery of a genetic change often found in thymus tumors in a gene that acts as a switch to activate many other genes. However, it was previously unclear how this subtle change in a gene called GTF2I leads to tumor formation. To answer this question, scientists used a trick. They modified the genetic information of the mice so that the affected animals activated a mutated switch in the thymus. A comparison with healthy mice made it possible to accurately monitor changes in the thymus of diseased animals.
There are two classes of cells in the thymus. The first type, called the stroma, provides a place for the second type of cells, the immune cells, to locate and mature until they can leave the thymus and perform the required control function in the body. A genetic change in the GTF2I gene found in tumors affects stromal cells, which are regenerated throughout life from so-called stem cells. Research shows that the mutated GTF2I gene prevents the regeneration of stromal cells. They stop halfway and therefore can only perform their supporting function for the formation of immune cells insufficiently. This effect becomes more pronounced with advancing age and may explain the accumulation of thymic cancer in the second half of life.
This discovery is significant in two ways. On the one hand, the researchers were able to identify a previously unknown intermediate stage in the process of stroma formation in the thymus, and on the other hand, they demonstrated that this implies a special susceptibility to malignant transformation. But the studies also show how drugs can be specifically tested to see if they can overcome this blockage and thereby normalize stroma formation again. “Our research shows once again how important animal experiments can be for progress in the understanding of human cancer. This especially applies to rare diseases, which are often not given enough attention,” says Thomas Boehm.
The researchers now want to further improve their animal model to better adapt it to the situation found in patients. In particular, they hope that detailed knowledge of the gradual development of tumors can be used to develop a stage-dependent therapy concept that could enable risk-adapted treatment of affected patients.