Slit2 signaling stimulates Ewing sarcoma growth

Kruthi Suvarna, Panneerselvam Jayabal, Xiuye Ma, Yuzuru Shiio

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)88-99
Number of pages12
JournalGenes and Cancer
Volume13
DOIs
StatePublished - 2022

Keywords

  • EWS::FLI1
  • Ewing sarcoma
  • Robo
  • Slit2
  • cdc42

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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