Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma

Abstract

Cancer cells must overcome anoikis (detachment-induced death) to successfully metastasize. Using proteomic screens, we found that distinct oncoproteins upregulate IL-1 receptor accessory protein (IL1RAP) to suppress anoikis. IL1RAP is directly induced by oncogenic fusions of Ewing sarcoma (EwS), a highly metastatic childhood sarcoma. IL1RAP inactivation triggers anoikis and impedes metastatic dissemination of EwS cells. Mechanistically, IL1RAP binds the cell surface system X c 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 EwS cells. Therefore, we define IL1RAP as a new cell surface target in EwS, which is potentially exploitable for immunotherapy. SIGNIFICANCEHere 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.Research.

Emerging roles of cystathionine β-synthase in various forms of cancer

“…In addition, several lines of recently emerging data underline the importance of CSE in various aspects of breast cancer biology including growth, metastasis and the development of multidrug resistance [ [220] , [221] , [222] , [223] , [224] , [225] ]. Finally, recent studies demonstrate the inhibitory effect of CSE inhibition and/or silencing in models of Ewing sarcoma [ 226 ] and glioma [ 227 ].…”

Chimeric antigen receptor T-cells targeting IL-1RAP: a promising new cellular immunotherapy to treat acute myeloid leukemia

“…In this work, we investigated IL-1RAP, a novel and unexplored AML cell surface marker expressed by leukemia cells but not by the healthy HSCs or the myeloid progenitors, not by the T and B lymphocytes, although it is expressed by circulating monocytes. 11 13 IL-1RAP, the accessory protein of the IL-1 receptor, plays a crucial role in immunity, inflammation, and cancer. It is involved in a tumor microenvironment that favors leukemia proliferation, 15 16 potentiates multiple oncogenic signaling pathways and oncogenic pathways, and contributes to AML oncogenesis.…”

Epigenetic and Transcriptional Signaling in Ewing Sarcoma—Disease Etiology and Therapeutic Opportunities

“…To identify regulators which are essential for metastasis, Zhang et al, utilized proteomic approaches and revealed a significant up-regulation of IL1RAP in cells resistant to anoikis (detachment-induced death) [ 116 ]. From this study, IL1RAP was identified as a direct target of EWSR1-FLI1 and a key driver of metastasis in EwS.…”