The Slit2 signaling pathway stimulates the growth of Ewing's sarcoma

Ewing sarcoma is a childhood bone and soft tissue carcinoma, most commonly EWS::FLI1
, caused by EWS::ETS fusion.
Since current cytotoxic chemotherapy does not improve survival in patients with metastatic or recurrent Ewing sarcoma, new and more effective targeted therapies
are needed.
While EWS::FLI1 is the main driver of Ewing sarcoma, EWS::FLI1 has been difficult to
target.

"A promising alternative is to identify and target molecular vulnerabilities
created by EWS::FLI1.
"

In this recent study, the researchers reported that EWS::FLI1 induced the expression of Slit2, a ligand for the Roundabout (Robo) receptor involved in axonal guidance and a variety of other developmental processes
.

"Using secretory ome proteomics, we found that EWS::FLI1 induces the expression
of Slit2.
We demonstrate that EWS::FLI1 binds to the gene promoter of Slit2 and activates its expression
.
”

EWS::FLI1 binds to the Slit2 gene promoter and stimulates Slit2 expression
.
Slit2 inactivates cdc42 and stabilizes BAF chromatin remodeling complexes, enhancing EWS::FLI1 transcriptional output
.
Silencing Slit2 has a strong inhibitory effect on anchorage-dependent and non-anchorage-dependent growth of Ewing sarcoma cells
.
Silencing the Slit2 receptors Robo1 and Robo2 also inhibited the growth
of Ewing sarcoma.
Their findings reveal a novel role in stimulating the growth of Ewing sarcoma by the Slit2 signaling pathway and suggest that the pathway can be targeted for therapy
.

Ewing sarcoma's dependence on Slit2 signaling offers excellent opportunities
for targeted therapies.
Although there is currently no drug inhibitor for the Slit-Robo signaling pathway, a radiolabeled anti-robo1 monoclonal antibody has been shown to inhibit xenograft tumor growth in hepatocellular carcinoma cells [28] and small cell lung cancer cells [29], suggesting that targeting the Slit-Robo pathway is feasible
.
Targeting the Slit2-Robo1/2 signaling pathway alone or in combination with the NELL2-Robo3 signaling pathway for Ewing's sarcoma warrants further study
.
”