Slit2 signaling stimulates Ewing sarcoma growth
Kruthi Suvarna1, Panneerselvam Jayabal1, Xiuye Ma1 and Yuzuru Shiio1,2,3
1 Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
2 Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
3 Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Correspondence:
Yuzuru Shiio, email:[email protected]
Keywords: cdc42; Ewing sarcoma; EWS::FLI1; Slit2; Robo
Received: August 08, 2022 Accepted: November 18, 2022 Published: December 14, 2022
Abstract
Ewing sarcoma is a cancer of bone and soft tissue in children driven by EWS::ETS fusion, most commonly EWS::FLI1. Because current cytotoxic chemotherapies are not improving the survival of those with metastatic or recurrent Ewing sarcoma cases, there is a need for novel and more effective targeted therapies. While EWS::FLI1 is the major driver of Ewing sarcoma, EWS::FLI1 has been difficult to target. A promising alternative approach is to identify and target the molecular vulnerabilities created by EWS::FLI1.
Here we report that EWS::FLI1 induces the expression of Slit2, the ligand of Roundabout (Robo) receptors implicated in axon guidance and multiple other developmental processes. EWS::FLI1 binds to the Slit2 gene promoter and stimulates the expression of Slit2. Slit2 inactivates cdc42 and stabilizes the BAF chromatin remodeling complexes, enhancing EWS::FLI1 transcriptional output. Silencing of Slit2 strongly inhibited anchorage-dependent and anchorage-independent growth of Ewing sarcoma cells. Silencing of Slit2 receptors, Robo1 and Robo2, inhibited Ewing sarcoma growth as well. These results uncover a new role for Slit2 signaling in stimulating Ewing sarcoma growth and suggest that this pathway can be targeted therapeutically.
