IGF-1 as the “Ignition Key” for Bone Cancer: Vienna-Based Research Team Unravels Origins of Ewing Sarcoma

A team of scientists led by Heinrich Kovar, Principal Investigator at St. Anna Children’s Cancer Research Institute (St. Anna CCRI) in Vienna, has uncovered a key mechanism in the development of Ewing sarcoma, one of the most aggressive forms of bone cancer. Published in the journal Cell Reports, the study reveals how a cancer-driving fusion gene interacts with hormonal changes during puberty to trigger this devastating disease.

Ewing sarcoma predominantly affects adolescents and has long challenged researchers. While the fusion gene EWS::FLI1 has been recognized as a hallmark of the disease, it has remained unclear why this genetic alteration alone does not always lead to cancer.

Now, Kovar’s team has shown that the onset of Ewing sarcoma requires more than just the fusion gene. It also depends on the presence of IGF-1 (Insulin-like Growth Factor 1), a growth hormone that surges during puberty. “Our findings suggest that the groundwork for Ewing sarcoma may be laid during embryonic development, but the disease itself is only triggered later—when hormonal signals like IGF-1 flip the switch,” explains Kovar. “IGF-1 acts like an ignition key, activating a previously silent predisposition.”

How the Tumor Gets Started

Using preclinical mouse models, the team was able to replicate the disease’s development. Bone precursor cells carrying the EWS::FLI1 gene alone did not form tumors. However, when these cells were exposed to elevated levels of IGF-1—mimicking the hormonal environment of human puberty—tumors developed that closely resembled human Ewing sarcoma in both appearance and behavior.

At the center of this process is the protein YAP1, which is activated by IGF-1. YAP1 works in tandem with TEAD transcription factors to switch on genes that promote cell proliferation and survival. “It’s a two-step safeguard,” says Kovar. “The fusion gene EWS::FLI1 may unlock certain genetic switches, but it’s YAP1 that actually flips them.”

This marks the first description of a two-tiered oncogenic mechanism: The genetic trigger (EWS::FLI1) requires the support of hormonal cues—specifically IGF-1-mediated activation of YAP1—during a precise developmental window to drive tumor formation.

The study doesn’t stop at uncovering the mechanism—it also points toward new treatment strategies. In laboratory experiments, the team tested inhibitors that block either the IGF-1 receptor (IGF-1R) or YAP1/TEAD activity. While each inhibitor alone had limited impact, their combined use significantly reduced tumor cell viability.

“Our data suggest that dual inhibition of IGF-1R and YAP1/TEAD may represent a promising therapeutic strategy—particularly for patients who no longer respond to standard treatments,” says Kovar.

Although drugs targeting IGF-1R already exist, they have shown limited success in clinical trials. This study may explain why: Without also suppressing YAP1/TEAD activity, those treatments likely left a critical escape pathway open. A combination approach could improve outcomes in future therapies.

Basic Research with Translational Promise

While this work remains in the realm of fundamental science, it lays the foundation for translational advances. The newly developed preclinical model offers a powerful platform for testing new drug combinations. Moreover, the identified mechanism represents a highly specific and potentially druggable vulnerability.

“We’ve uncovered a fundamental mechanism that likely plays a central role in many cases of Ewing sarcoma,” says Kovar. “This opens up entirely new ways of understanding—and eventually treating—this aggressive disease.”

An International Collaboration

The study was a collaborative effort between St. Anna Children’s Cancer Research Institute, the Medical University of Vienna, and the Ludwig Boltzmann Institute for Cancer Research. It was supported by funding from the European Union, Alex’s Lemonade Stand Foundation, and the Austrian Science Fund (FWF).