Researchers Find the Cell of Origin of Ewing Sarcoma

One of the great mysteries of Ewing sarcoma, a highly aggressive pediatric tumor, is where it originates. This information is vital for finding more effective ways to treat it. However, this question now appears to have been answered, thanks to the work of a multicenter team led by the Hospital del Mar Research Institute and Institut de Recerca Sant Joan de Déu (IRSJD), published in the journal Nature Communications. The study opens the door to discovering what factors trigger tumor progression and its potential vulnerabilities.

Although the cure rate ranges between 60 and 70%, the toxicity of current chemotherapy treatments leads to side effects in children. Knowing where the disease originates, the cell that is the source, can allow for more targeted and careful approaches, as explained by Dr. Inmaculada Hernández-Muñoz, a researcher with the Research Group on Inflammatory and Neoplastic Dermatological Diseases at HMRIB. "Now that we have identified the cell that originates the tumor, the next step is to determine what factors cause a cell that, in principle, has no growth advantage, to acquire that trait," she adds.

Early presence in fetal development

One of the main characteristics of Ewing sarcoma is that, unlike most tumors, it is caused by a single oncogene. Two genes combine to generate a new one, acquiring new functions that confer the capacity to develop the disease when expressed in embryonic mesenchymal stem cells, as demonstrated by the new study. These are the cells that form the mesenchyme, from which embryonic tissue, including muscle and connective tissue, blood vessels, and lymphatic vessels, are derived.

The study now published has, for the first time, succeeded in reproducing this mechanism. In collaboration with the laboratory led by Dr. Ángel Raya at the Center for Regenerative Medicine in Barcelona, ​​human embryonic mesenchymal cells were generated and purified, into which the oncogen that causes Ewing sarcoma was introduced. Although these cells do not exhibit tumor characteristics in vitro, when inoculated into mice they generate tumors similar to human Ewing sarcoma, maintaining the cellular and transcriptional patterns characteristic of the sarcoma.

In this regard, Dr. Hernández-Muñoz pointed out that "we are talking about a mesenchymal cell that, at a very early stage of embryonic development, acquires the oncogen that can later generate Ewing sarcoma." In other words, "the cell of origin of Ewing sarcoma is already present in the fetus during its intrauterine development, and our hypothesis is that upon reaching puberty, hormonal factors cause this cell, which already possesses the oncogen, to generate the tumor."

With these results, Dr. Hernández-Muñoz asserts that "we have an experimental model to understand the structure of this cell and to study the changes it undergoes until it becomes tumorous." This will allow researchers to analyze its strengths and weaknesses, as well as the factors that trigger tumor proliferation and spread, in order to develop future treatments specifically designed to prevent them.

In this regard, Dr. Jaume Mora, scientific director of the Pediatric Cancer Center Barcelona (PCCB) at SJD Barcelona Children’s Hospital (HSJD) and head of the Sarcomas and Neuroblastoma research group at the Institut de Recerca Sant Joan de Déu (IRSJD), points out that "this discovery represents a fundamental advance in the understanding of Ewing sarcoma. Identifying the tumor process opens new avenues for the development of more targeted and less toxic therapies for pediatric patients. Our goal is for this knowledge to translate into more effective treatments with fewer side effects for children and adolescents affected by this disease."