STAG2 loss linked to increased aggression in Ewing sarcoma

Ewing sarcoma is a tumor of the bones and soft tissues that occurs in children and young people. Like all childhood cancers, it is rare – 9 to 10 cases per million inhabitants per year – but it is very aggressive. 25% of patients do not respond well to regular therapy and they often experience relapses.

A new study led by Ana Losada, head of the Chromosomal Dynamics Group at Spain's National Cancer Research Centre (CNIO), identifies several mechanisms that increase the aggressiveness of Ewing sarcoma, promoting metastasis and leading to a poorer prognosis.

This finding opens up new avenues for seeking treatments, since it "provides a list of potential [prognosis] biomarkers and therapeutic targets," the authors write in EMBO Reports. Ana Cuadrado is co-corresponding author of the study and Daniel Giménez-Llorente is the first author.

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

Ana Cuadrado, corresponding author of the study, explains that 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 tumour aggressiveness".

A key protein for life

STAG2 is part of a complex of proteins 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 genes –their expression–.

When the cell divides, it duplicates its chromosomes so that each of the daughter cells gets a copy of the DNA; during that duplication, the chromosomes are arranged in an X, and cohesin is the ring that binds them together at the centre (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 arrangement, which is important for the information of the genes to be correctly read (all cells have the same genes, and their differences – some of them will build skin, some others eyes, or muscl...–are due to the fact that each cell type reads or expresses different genes according to their function).

Errors in the reading of genes

The paper published in EMBO Reports shows that when cohesin STAG2 is missing, DNA folds incorrectly, causing failures in the expression of many genes.

"The cohesin that carries 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 turn them more aggressive."

Influence on the immune response

The importance of identifying more genes – independent of the oncogene– affected by the absence of STAG2 "is that it opens the door to investigate how each of them contributes to the aggressiveness of tumours," explains Losada.

For example, future studies comparing the immune response of patients with and without STAG2 mutations may help us understand whether tumours without STAG2 are better able to elude the immune system. This knowledge would be very useful when applying immunotherapy for Ewing sarcoma.

In addition to altering gene expression, the loss of STAG2 could affect the stability of the genome itself, as this is another function of the cohesin complex. That is, there could be several mechanisms affected by the loss of STAG2, and those that contribute in turn to the poorer prognosis of the disease. We need to shed light on each of these mechanisms, "in order to provide novel treatment options for cohesin-mutant patients," the study says.

This research has been funded by the Spanish Cancer Association (AECC) and the Spanish Research Agency (AEI).