BIF Fellowship: Building Ewing Sarcoma Models from Scratch

Due to a lack of good models and an unknown cell of origin, Ewing sarcoma still poses a great puzzle in childhood cancer research. Hana Bernhardova, a PhD student in Eleni Tomazou’s group, has now received the prestigious PhD Fellowship from the Boehringer Ingelheim Fonds to tackle this problem.

Ewing sarcoma is among the most aggressive pediatric tumors, affecting bone and soft tissue. Although its genetic driver, EWSR1::FLI1, has already been identified, treatment still relies on intensive chemotherapy which is associated with severe long-term side effects. Progress has been slow because researchers still lack a crucial piece of the puzzle: the developmental and cellular origin of the disease. Understanding which cell type can give rise to Ewing sarcoma is essential to uncover its biology and develop more targeted therapies.

Fusion oncogenes: the drivers of Ewing Sarcoma

Fusion oncogenes arise when two genes fuse together in a rare but catastrophic genetic event. The resulting hybrid gene produces faulty instructions that can push a healthy cell to divide uncontrollably, initiating cancer formation. What makes these fusion oncogenes so intriguing is their specificity: each one drives only particular cancer types and can transform only certain cell types. In other words, the same fusion gene can be harmless in one cellular context but highly oncogenic in another — a clue that may hold the key to understanding Ewing sarcoma.

A “build-to-understand” strategy to model Ewing sarcoma

With her Boehringer Ingelheim Fonds (BIF) PhD Fellowship, Hana Bernhardova aims to uncover the exact cellular conditions that, together with the fusion oncogene, give rise to Ewing sarcoma. Working in Eleni Tomazou’s lab at St. Anna CCRI, she follows a “build-it-to-understand” approach, creating Ewing sarcoma models from scratch. Using human pluripotent stem cells, she can generate different potential cells of origin and test how they respond when the EWSR1::FLI1 fusion gene is introduced.

Once the susceptible cellular context is identified, Hana will trace the entire course of tumor evolution — from the first transformed cell to tumor formation and metastasis — in mouse models. This comprehensive reconstruction could expose molecular mechanisms that allow the tumor to progress and reveal new vulnerabilities for therapeutic intervention.

Filling the model gap in fusion-driven cancer research

A persistent challenge in Ewing sarcoma research has been the absence of reliable preclinical models. Without knowing the correct cell of origin, it has been impossible to mimic disease initiation and progression accurately. Bernhardova’s systematic strategy directly addresses this limitation by identifying the precise developmental context required for transformation. Her research could redefine how scientists model and understand pediatric cancers at their very beginning.