New discoveries about the EWS-FLI oncogene involved in the development of Ewing's tumor
Researchers from IRSJD · SJD Barcelona Children's Hospital and IRB Barcelona have successfully developed Drosophila models expressing the EWS-FLI oncogene at varying levels, overcoming previous toxicity challenges and enabling detailed study of Ewing sarcoma's oncogenic pathways.
Ewing sarcoma, a cancer that arises in bone or soft tissue, has long posed a challenge to researchers due to the limitations of existing animal models. The primary obstacle has been the extreme toxicity of EWS-FLI, the oncogene driving the disease. This toxicity typically results in cell death when EWS-FLI is expressed, making it difficult to establish viable research models.
In response to this challenge, a collaborative effort between researchers from Dr. Jaume Mora’s team at IRSJD · SJD Barcelona Children’s Hospital and Dr. Cayetano González at IRB Barcelona, focused on developing a Drosophila model for Ewing sarcoma.
This collaboration led to the discovery of a mutant variant of the human oncogene that circumvented the toxicity issue and made it possible to show that the main oncogenic pathways triggered by EWS-FLI in human Ewing sarcoma cells can be realistically reproduced in genetically engineered fly models (Molnar et. al., 2020). However, the quest for a Drosophila study model based on unmodified EWS-FLI expression remained open.
"Ewing sarcoma happens to be the second most common paediatric bone cancer, and there's no specific treatment for this disease as of yet. This is what motivates a lot of the research effort into developing an animal model that will allow studying the disease.", states Serena Mahnoor, PhD student at IRB Barcelona and first author of the study.
In their new study, through innovative strategies, the researchers have met this challenge and succeeded at generating a series of fly models that express EWS-FLI at varying levels, providing a nuanced tool for studying the oncogene's effects.
This breakthrough has allowed researchers to investigate the relationship between EWS-FLI protein levels and its key functions. Notably, they discovered that different functions of EWS-FLI exhibit distinct kinetics relative to protein concentration.
This finding aligns with observations from human Ewing sarcoma tumours, where EWS-FLI levels are known to vary significantly between cells within the same tumour, leading to diverse cellular responses.
The development of these Drosophila models offers a valuable platform for studying the consequences of varying EWS-FLI levels, mirroring the heterogeneity observed in human tumours. This research tool has the potential to accelerate the search for specific therapies, addressing a critical need in Ewing sarcoma treatment.
This research, recently published in Open Biology, represents a significant step forward in understanding the complex dynamics of this aggressive malignancy.
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New Drosophila models offer key insights into Ewing sarcoma oncogene function. IRB Barcelona.
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The work, published in Open Biology, holds promise for accelerating the development of targeted therapies for Ewing sarcoma.