Scientists are developing an unprecedented animal model to study Ewing's sarcoma

Scientists are developing an unprecedented animal model to study Ewing's sarcoma

Ewing's sarcoma is the second most common bone tumor in children, adolescents and young adults. There is no specific treatment for this disease and current treatment is still limited to surgery, radiation therapy and chemotherapy. The long-term survival of patients with metastatic or relapsed Ewing sarcoma is very low.

Ewing's sarcoma is caused by a single oncogene that results from the fusion of two genes. Although a variety of genes can be involved, EWSR1 and FLI1 and the resulting cancer-causing oncogene, known as EWS-FLI, are responsible in the majority of patients. Unlike most other cancers, all attempts to develop experimental animal models of Ewing's sarcoma in mice (which express the EWS-FLI oncogene) have failed.

Inspired by the need for a genetically controllable model that could be used to study the disease, researchers led by Dr. Cayetano González, ICREA Research Professor at IRB Barcelona, ​​and Dr. Jaume Mora, scientific director at the SJD Pediatric Cancer Center Barcelona (PCCB). ) have developed transgenic Drosophila strains that express a mutated variant of the human oncogene called EWS-FLIFS. Remarkably, they found that expression of the human EWS-FLIFS protein in certain types of Drosophila cells triggers the same oncogenic signaling pathways known to be responsible for the oncogenic activity of EWS-FLI in human patients.

Illuminating two oncogenic signaling pathways

Building on their new transgenic Drosophila line, the authors rewired two oncogenic pathways used by EWS-FLI so that, when triggered by the presence of EWS-FLIFS, they result in the expression of a fluorescent protein that would otherwise never be expressed. Therefore, the researchers use fluorescence as a measure of the oncogenic activity of EWS-FLI instead of tumor growth.

This simple genetic trick greatly facilitates the performance of extensive genetic and chemical screens to identify “modifiers” that inhibit the oncogenic activity of EWS-FLI as inhibitors of the appearance of fluorescence.”

Dr. Cristina Molnar, postdoctoral researcher at IRB Barcelona and first author of the study

Genetic screens based on this new model will make it possible to discover critical proteins required for the exercise of the oncogenic function of EWS-FLI. This allows us to expand our knowledge of the molecular basis of the disease and identify new putative therapeutic targets. Chemical screenings can identify compounds that could serve as lead molecules for the development of therapeutic drugs.

A solid collaboration between IRB Barcelona and PCCB

Those from Dr. Gonzalez and Dr. Mora-led laboratories have been working together since 2019 to explore the use of Drosophila as a model for childhood cancer.

Ongoing efforts in this collaboration include genetic and chemical screens based on the Ewing sarcoma model and the development of new Drosophila models for other types of childhood cancer.

Source:

Institute of Biomedical Research (IRB Barcelona)

Reference:

Molnar, C., et al. (2022) The human EWS-FLI protein recapitulates in Drosophila the neomorphic functions that induce tumorigenesis of Ewing's sarcoma. PNAS Nexus. doi.org/10.1093/pnasnexus/pgac222.

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