New avenues of research against Ewing sarcoma

Ewing’s sarcoma is a bone and soft tissue tumor that occurs in children and young people. Like all pediatric cancers, it is rare (it has a prevalence of between 9 and 10 cases per million inhabitants per year) but it is very aggressive. 25% of patients do not respond well to usual therapy and frequently experience recurrences.

A new study led by Ana Losada, head of the Chromosome Dynamics Group at the National Cancer Research Center (CNIO) in Spain, identifies several mechanisms that increase the aggressiveness of Ewing sarcoma, by promoting metastasis and leading to a worse outcome. the disease. Ana Cuadrado and Daniel Giménez-Llorente, both from the CNIO, are co-authors of the study.

What was discovered in this study opens new avenues for searching for treatments, since it provides a list of potential biomarkers [pronóstico] and therapeutic targets, as pointed out by the authors of the study.

Ewing sarcoma is caused by the abnormal fusion of two genes, resulting in an oncogene. The protein produced by this oncogene causes the expression of genes that promote tumor development. It was already known that the lack of a protein, called STAG2, amplifies the harmful effect of this oncogene, but the new study now shows that there are also alterations in the reading of many other genes.

As Ana Cuadrado explains, the absence of the STAG2 protein also modifies the expression of other genes that do not depend on the oncogene, and these changes also increase the aggressiveness of the tumor.

A key protein for life

STAG2 is part of a protein complex essential for life, cohesin, discovered in vertebrates by Losada in the late 90s. Cohesin is key in cell division and during the process of reading or expressing genes.

When the cell divides, it duplicates its chromosomes so that the daughter cells have one copy of the DNA; During this duplication the chromosomes are arranged in X, and cohesin is the ring that holds them together in the center (hence its name).

The rest of the time, when the cell is not dividing, cohesin generates bonds that help the DNA to fold and acquire the appropriate spatial conformation, important so that the information from the genes can be read correctly (all cells have the same genes, and their differences (there are skin, eye, muscle…) are due to the fact that each cell type reads or expresses different genes according to their function).

From left to right: Ana Losada, Ana Cuadrado and Daniel Giménez-Llorente, from the research team. (Photo: Laura M. Lombardía / CNIO)

Errors in reading genes

The new study shows that when the cohesin STAG2 is missing, DNA folds incorrectly, causing failures in the expression of many genes.

“The cohesin carried by STAG2 moves along the DNA forming bonds that facilitate physical contact between elements that control the reading of many genes; If it disappears, gene expression becomes more difficult,” says Losada. “The cells survive, but with many aberrations that make them more aggressive.”

The importance of having identified more genes affected by the lack of STAG2, independent of the oncogene, “is that it opens the door to investigating how each of them contributes to the aggressiveness of tumors,” explains Losada.

For example, future studies comparing the immune response of patients with and without STAG2 mutations may help understand whether tumors without STAG2 evade the immune system better. This knowledge would be very useful when applying immunotherapy against Ewing sarcoma.

In addition to altering gene expression, the loss of STAG2 could affect the stability of the genome itself, since this is another of the functions of the cohesin complex. That is, there could be several mechanisms affected by the loss of STAG2, and those that simultaneously contribute to the worse prognosis of the disease. It is necessary to elucidate each of these mechanisms to provide new treatment options for patients with mutations that affect cohesin.

The study is titled “STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1”. And it has been published in the academic journal EMBO Reports. (Source: CNIO)