Metabolism
Do sugar-coated proteins feed Ewing sarcoma?
Open access · cc by · source: Europe PMC
A zebrafish EWSR1-FLI1 model produced CD99+ small-round-cell tumors with MAPK/ERK on; blocking heparan sulfate with Surfen reduced ERK1/2 signaling and tumorigenicity in vitro and in vivo.
How this study connects
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Study at a glance
- Design
- Animal / in-vitro — Cre-inducible human EWSR1-FLI1 zebrafish model of Ewing sarcoma plus in-vitro/in-vivo tests of the heparan sulfate antagonist Surfen
- N
- N=524 · Survival analysis in 524 EWSR1-FLI1 animals; controls included uninjected N=528, GFP N=328, Cre N=304; tumor incidence also scored in n=77 Cre-injected fish
- Population
- Wild-type zebrafish embryos/larvae expressing human EWSR1-FLI1, with supporting Ewing sarcoma cell assays
- Outcome
- SRBCT formation, MAPK/ERK activity, and whether Surfen lowers ERK signaling and tumorigenicity
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Inspect source passages
Do sugar-coated proteins feed Ewing sarcoma?
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Survival analysis in 524 EWSR1-FLI1 animals vs uninjected N=528.
we performed survival analysis in a group of 524 animals. Uninjected embryos ( N = 528), embryos injected with ubi:RSG-EWSR1-FLI1 and GFP mRNA ( N = 328) and embryos injected with ubi:RSG and Cre mRNA ( N = 304) were used as negative controls.
eGFP+ tumor incidence scored in n=77 Cre-injected zebrafish.
Incidence of eGFP+ tumors detected in Ubi:RSG-EWSR1-FLI1; Cre RNA ( n = 77) injected zebrafish versus Ubi:RSG-EWSR1-FLI1; eGFP RNA ( n = 142) and uninjected controls ( N = 150)
Key findings
EWSR1-FLI1 caused rapid, high-penetrance SRBCTs that expressed canonical targets and CD99. Tumor growth tracked MAPK/ERK activation linked to dysregulated ECM and HSPG catabolism. Surfen reduced ERK1/2 signaling and decreased tumorigenicity. Survival analysis used 524 EWSR1-FLI1 animals vs large control groups.
Methodology
Built Cre-inducible human EWSR1-FLI1 expression in wild-type zebrafish, characterized SRBCTs and ECM/heparan sulfate metabolism, then treated with the heparan sulfate antagonist Surfen in cells and fish.
Limitations
A zebrafish/cell study cannot yet show that Surfen is a safe human therapy; Ewing remains without an approved molecularly targeted drug from this paper alone.
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