PXD019009-1

PXD019009 is an original dataset announced via ProteomeXchange.

Title	IL1RAP augments cysteine metabolism to promote ferroptosis resistance and metastasis in Ewing sarcoma
Description	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.
HostingRepository	PRIDE
AnnounceDate	2021-05-25
AnnouncementXML	Submission_2021-05-25_14:34:09.848.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christopher Hughes
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion ETD

Revision	Datetime	Status	ChangeLog Entry
0	2020-05-06 01:10:52	ID requested
⏵ 1	2021-05-25 14:34:10	announced

Zhang HF, Hughes CS, Li W, He JZ, Surdez D, El-Naggar AM, Cheng H, Prudova A, Delaidelli A, Negri GL, Li X, Ø, rum-Madsen MS, Lizardo MM, Oo HZ, Colborne S, Shyp T, Scopim-Ribeiro R, Hammond CA, Dhez AC, Langman S, Lim JKM, Kung SHY, Li A, Steino A, Daugaard M, Parker SJ, Geltink RIK, Orentas RJ, Xu LY, Morin GB, Delattre O, Dimitrov DS, Sorensen PH, Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma. Cancer Discov, 11(11):2884-2903(2021) [pubmed]

submitter keyword: IL1RAP, cysteine metabolism, TMT, Ewing sarcoma

Poul Sorensen
contact affiliation	Senior Scientist, Molecular Oncology, BC Cancer Research Centre/University of British Columbia
contact email	psorensen@bccrc.ca
lab head
Christopher Hughes
contact affiliation	BC Cancer Agency
contact email	chughes@bcgsc.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD019009
     1. Label: PRIDE project
     2. Name: IL1RAP augments cysteine metabolism to promote ferroptosis resistance and metastasis in Ewing sarcoma