Cancer cells must overcome anoikis (detachment-induced death) to successfully metastasize. Using proteomic screens, we found that distinct
oncoproteins upregulate
IL1 receptor accessory
protein (IL1RAP) to suppress anoikis. IL1RAP is directly induced by oncogenic fusions of
Ewing sarcoma, a highly metastatic childhood
sarcoma. IL1RAP inactivation triggers anoikis and impedes metastatic dissemination of
Ewing sarcoma cells. Mechanistically, IL1RAP binds the cell-surface system Xc - transporter to enhance exogenous
cystine uptake, thereby replenishing
cysteine and the
glutathione antioxidant. Under
cystine depletion, IL1RAP induces
cystathionine gamma lyase (CTH) to activate the transsulfuration pathway for de novo
cysteine synthesis. Therefore, IL1RAP maintains
cyst(e)ine and
glutathione pools, which are vital for redox homeostasis and anoikis resistance. IL1RAP is minimally expressed in pediatric and adult normal tissues, and human anti-IL1RAP
antibodies induce potent antibody-dependent cellular cytotoxicity of
Ewing sarcoma cells. Therefore, we define IL1RAP as a new cell-surface target in
Ewing sarcoma, which is potentially exploitable for
immunotherapy. SIGNIFICANCE: Here, we identify
cell-surface protein IL1RAP as a key driver of
metastasis in
Ewing sarcoma, a highly aggressive childhood
sarcoma. Minimal expression in pediatric and adult normal tissues nominates IL1RAP as a promising target for
immunotherapy.See related commentary by Yoon and DeNicola, p. 2679.This article is highlighted in the In This Issue feature, p. 2659.