A new function of EWSR1::FLI1 uncovered in Ewing sarcoma
Ewing sarcoma is a rare and highly aggressive pediatric cancer that arises in the bones and soft tissues. For over three decades, researchers have known that it is driven by an unusual fusion protein, EWSR1::FLI1, which has been studied almost exclusively for its role as a “rogue” transcription factor, activating harmful genetic programs that fuel tumor growth.
But a team led by Bartimée Galvan in the laboratory of Prof Franck Dequiedt (GIGA-Molecular & Computational Biology) has now shown that this view is incomplete. In a study published in Nature Communications, they reveal that this protein acts well beyond DNA control: it also directly targets the genetic messages (mRNAs) produced by the cell. By altering their stability, it profoundly changes the behavior of cancer cells.
The mechanism is ingenious: EWSR1::FLI1 hijacks two key players in mRNA fate. On one hand, it recruits the CCR4-NOT complex, which initiates mRNA degradation. On the other, it “flips” the HuR protein—normally tasked with protecting mRNAs—into acting as a degradation factor instead. As a result, the messages that hinder tumor cell survival and proliferation are selectively destroyed, reinforcing the cancer’s aggressiveness.
This is the first time an oncogenic transcription factor has been shown to directly control mRNA decay. The discovery reshapes our understanding of how EWSR1::FLI1 drives cancer and opens new therapeutic avenues: the researchers found that Ewing sarcoma cells become particularly vulnerable to HuR inhibition.
By showing that EWSR1::FLI1 controls both gene expression and mRNA stability, this research highlights a novel weakness that could be exploited not only in Ewing sarcoma, but also in other related fusion-driven cancers.
Reference
Galvan B, Ongena L, Bruyr J, Fettweis G, Lucarelli E, Lavergne A, Mariavelle E, O'Grady TM, Hassoun ZEO, Claes M, Dubois L, Lee KAW, Kruys V, Gueydan C, Durand J, Hervouet E, Geyer FH, Banito A, Imle R, Mao L, Jayavelu AK, Grünewald TGP, Cidre-Aranaz F, Twizere JC, Dequiedt F.
Nat Commun. 2025 Jul 16;16(1):6537. doi: 10.1038/s41467-025-61725-x.
