Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma.
Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma.
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DOI：
10.1158/2159-8290.cd-20-1690
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发表时间：
2021-11
期刊：
影响因子：
28.2
通讯作者：
Sorensen PH
中科院分区：
文献类型：
--
作者：
Zhang HF;Hughes CS;Li W;He JZ;Surdez D;El-Naggar AM;Cheng H;Prudova A;Delaidelli A;Negri GL;Li X;Ørum-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
表面IL1RAP维持囊泡(E)和谷胱甘肽池，以阻止失巢凋亡和促进尤文肉瘤的转移扩散，在正常组织中的极低表达表明IL1RAP是一个有希望的免疫治疗靶点。癌细胞必须克服脱落引起的死亡才能成功转移。利用蛋白质组学筛选，我们发现不同的癌蛋白上调IL1受体辅助蛋白(IL1RAP)以抑制失巢凋亡。IL1RAP是由尤文肉瘤的致癌融合直接诱导的，尤文肉瘤是一种高度转移的儿童肉瘤。IL1RAP失活触发失巢细胞并阻碍尤文肉瘤细胞的转移扩散。在机制上，IL1RAP结合细胞-表面系统XC−转运体，以增强外源半胱氨酸的摄取，从而补充半胱氨酸和谷胱甘肽抗氧化剂。在半胱氨酸耗竭的情况下，IL1RAP诱导胱硫氨酸伽马裂解酶(CTH)激活半胱氨酸从头合成的跨硫途径。因此，IL1RAP维持胞囊(E)和谷胱甘肽池，这对氧化还原动态平衡和抗失巢凋亡至关重要。IL1RAP在儿童和成人正常组织中低水平表达，人源性抗IL1RAP抗体可诱导尤文肉瘤细胞产生强大的抗体依赖性细胞毒作用。因此，我们将IL1RAP定义为尤文肉瘤的一个新的细胞表面靶点，具有潜在的免疫治疗潜力。在这里，我们确定细胞表面蛋白IL1RAP是尤文肉瘤转移的关键驱动因素，尤文肉瘤是一种高度侵袭性的儿童肉瘤。IL1RAP在儿童和成人正常组织中的极低表达表明IL1RAP是一个有希望的免疫治疗靶点。见Yoon和DeNicola的相关评论，第2679页。本文在本期专题中重点介绍，第2659页
Surface IL1RAP maintains cyst(e)ine and glutathione pools to block anoikis and facilitate metastatic dissemination in Ewing sarcoma, and minimal expression in normal tissues nominates IL1RAP as a promising immunotherapy target. 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. 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