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Mutated protein keeps cancer program of childhood connective tissue tumors in infinitive loop

No. 46c3 | 21/09/2023

An altered protein, which is also used for the diagnosis of malignant connective tissue tumors in adolescents and young adults, contributes decisively to the development and aggressive course of these tumors. This has been discovered by a team of researchers at the Hopp Children's Cancer Centre Heidelberg (KiTZ) and the German Cancer Research Centre (DKFZ). The current study uncovers a new molecular circuit that could also be a promising therapeutic target for other cancers.
The Hopp Children's Cancer Center Heidelberg (KiTZ) is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD) and the University of Heidelberg (Uni HD).

© Nezha Benabdallah/KiTZ

Synovial sarcoma is a malignant connective tissue tumor that is one of the most common soft tissue sarcomas in adolescents and young adults. It often grows in the body at junctions with tendons and joint capsules, for example in the knee. Those affected have a comparatively poor long-term prognosis. In about half of them, the cancer progresses aggressively and forms metastases. Most of the young patients then do not survive the disease.

The research group led by Ana Banito from the Hopp Children's Cancer Centre Heidelberg (KiTZ) and the German Cancer Research Centre (DKFZ) has been able to show how these tumors manage to continuously maintain a genetic program so that cancer cells develop instead of normal cells.

A fusion of two genes, which is typical for this type of sarcoma, creates an altered protein, a so-called fusion protein, which plays an important role in the regulation of developmental genes. Parts of the SS18- and SSX genes, which are normally located on completely different chromosomes, attach to each other and combine. This gene fusion is currently considered one of the most important features for the diagnosis of synovial sarcomas and seems to be decisive for their growth and development. What exactly it does at the molecular level, however, remains unclear.

Ana Banito and her research team have discovered that only a small end piece of the SS18-SSX fusion protein is responsible for switching on certain developmental genes that are normally "silent". Such silent regions in the genome are characterized by certain chemical marks, including the polypeptide ubiquitin. These so-called epigenetic marks signal to the cell, "Do not read this genetic code!" However, because of the crucial end piece, the SS18-SSX protein can dock to these regions and activate the genes anyway. "By turning on these genes, the normal developmental process of the cells is blocked. Instead of differentiating into connective tissue cells, the cells remain in a division-active precursor stage and become tumor cells," explains Ana Banito.

As the studies shows, the SSX end piece is so crucial that it is able switch on these developmental genes even when fused to other proteins, other than SS18. But that's not all: as the scientists' investigations in mice and cell cultures show, the end piece of the fusion protein also binds and stabilizes another protein complex that is responsible for attaching ubiquitin to the silent genes. The protein complex PRC1.1. "By ensuring that ubiquitination is maintained at the crucial cancer genes, the SS18-SSX protein can also repeatedly dock to activate these genes. It thus maintains a genetic prog ram typical of synovial sarcomas in a continuous loop, so to speak," Banito describes another important result of her current study.

The research team around Banito now wants to investigate in further studies whether the molecular circuit with ubiquitin-depositing complexes and SS18-SSX could be a new therapeutic target to successfully treat synovial sarcomas.

Original publication
Benabdallah, N.,S. et al. Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability. In: Nature Structural & Molecular Biology (Online Publication September 21, 2023) DOI: 10.1038/s41594-023-01096-3


With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany’s largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.

To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:

  • National Center for Tumor Diseases (NCT, 6 sites)
  • German Cancer Consortium (DKTK, 8 sites)
  • Hopp Children's Cancer Center (KiTZ) Heidelberg
  • Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ
  • DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
  • National Cancer Prevention Center (jointly with German Cancer Aid)
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.


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