| Autor: |
Poul H. Sorensen, Dimiter S. Dimitrov, Olivier Delattre, Gregg B. Morin, Li-Yan Xu, Rimas J. Orentas, Ramon I. Klein Geltink, Seth J. Parker, Mads Daugaard, Anne Steino, Amy Li, Sonia H.Y. Kung, Jonathan K.M. Lim, Sofya Langman, Anne-Chloe Dhez, Colin A. Hammond, Renata Scopim-Ribeiro, Taras Shyp, Shane Colborne, Htoo Zarni Oo, Michael M. Lizardo, Maj Sofie Ørum-Madsen, Xiaojun Li, Gian Luca Negri, Alberto Delaidelli, Anna Prudova, Hongwei Cheng, Amal M. El-Naggar, Didier Surdez, Jian-Zhong He, Wei Li, Christopher S. Hughes, Hai-Feng Zhang |
| Rok vydání: |
2023 |
| 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 |
| Externí odkaz: |
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