IL1RAP augments cysteine metabolism to promote ferroptosis resistance and metastasis in Ewing sarcoma

ABSTRACT: Aggressive cancer cells must adapt and overcome oxidative stress encountered during the metastatic cascade to successfully disseminate. In this work, a combination of proteomic approaches is used to identify the IL1 receptor accessory protein (IL1RAP) as an in vitro suppressor of anoikis (detachment-induced cell death). IL1RAP is found to be a direct transcriptional target of characteristic Ewing sarcoma (EwS) oncogenic fusions and an important overall mediator of redox homeostasis through the maintenance of glutathione (GSH) synthesis. IL1RAP is found to control intracellular cysteine and GSH synthesis in EwS via binding to CD98 and SLC7A11 of the system Xc- transporter to enhance exogenous cystine uptake for cysteine conversion. In addition, IL1RAP transcriptionally controls cystathionine gamma lyase (CTH), an enzyme that is crucial for de novo cysteine synthesis via the transsulfuration pathway. IL1RAP or CTH depletion is found to susceptibility to ferroptosis and dramatically reduced overall lung metastasis of EwS xenografts in mice. Together, this work describes the critical role of IL1RAP in the maintenance of redox homeostasis through cysteine metabolism in EwS, and identifies a previously unidentified pathway in the pathobiology of this disease.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Cell Culture

DISEASE(S): Peripheral Primitive Neuroectodermal Tumor

SUBMITTER: Christopher Hughes  

LAB HEAD: Poul Sorensen

PROVIDER: PXD019009 | Pride | 2021-05-25

REPOSITORIES: Pride