Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma
Autor: | Amy Li, Anna Prudova, Amal El-Naggar, Hongwei Cheng, Dimiter S. Dimitrov, Jian-Zhong He, Colin A. Hammond, Seth J. Parker, Rimas J. Orentas, Taras Shyp, Renata Scopim-Ribeiro, Xiaojun Li, Olivier Delattre, Christopher S. Hughes, Alberto Delaidelli, Mads Daugaard, Sonia H.Y. Kung, Htoo Zarni Oo, Jonathan K M Lim, Wei Li, Poul H. Sorensen, Hai-Feng Zhang, Anne-Chloe Dhez, Michael M. Lizardo, Shane Colborne, Anne Steino, Didier Surdez, Sofya Langman, Ramon I. Klein Geltink, Gregg B. Morin, Maj Sofie Ørum-Madsen, Li-Yan Xu, Gian Luca Negri |
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Rok vydání: | 2020 |
Předmět: |
Adult
Proteomics Cell Transsulfuration pathway Sarcoma Ewing 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Cell Line Tumor medicine Humans Anoikis Child 030304 developmental biology 0303 health sciences Chemistry Cystathionine gamma-lyase Receptors Interleukin-1 Glutathione medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research Interleukin-1 Receptor Accessory Protein Cysteine |
Zdroj: | Cancer discovery. 11(11) |
ISSN: | 2159-8290 |
Popis: | 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 |
Databáze: | OpenAIRE |
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