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Proteomic Screens for Suppressors of Anoikis Identify IL1RAP As a Promising Surface Target in Ewing Sarcoma

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Proteomic Screens for Suppressors of Anoikis Identify IL1RAP As a Promising Surface Target in Ewing Sarcoma Author Manuscript Published OnlineFirst on May 21, 2021; DOI: 10.1158/2159-8290.CD-20-1690 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Proteomic screens for suppressors of anoikis identify IL1RAP as a promising surface target in Ewing sarcoma Hai-Feng Zhang1,2, Christopher S Hughes1,2, Wei Li3, Jian-Zhong He4, Didier Surdez5,6, Amal M El- Naggar1,2, Hongwei Cheng2,7, Anna Prudova2,8, Alberto Delaidelli1,2, Gian Luca Negri8, Xiaojun Li2, Maj Sofie Ørum-Madsen9, Michael M Lizardo2, Htoo Zarni Oo9, Shane Colborne8, Taras Shyp1,2, Renata Scopim-Ribeiro1,2, Colin A Hammond10, Anne-Chloe Dhez1,2, Sofya Langman1,2, Jonathan KM Lim1,2, Sonia HY Kung9, Amy Li1,2, Anne Steino2, Mads Daugaard9, Seth J Parker1,11, Ramon I Klein Geltink1,11, Rimas J Orentas12, Li-Yan Xu4, Gregg B Morin8,13, Olivier Delattre#,5, Dimiter S Dimitrov#,3, Poul H Sorensen*,1,2 1Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T1Z4, Canada. 2Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada. 3Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA. 4Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong 515041, China. 5Centre de recherche de l'Institut Curie, Paris 75248, France. 6Balgrist University Hospital, University of Zurich, Zurich, Switzerland. 7Modelling and translation Laboratory, Xinxiang Medical University, Xinxiang, Henan 453003, China. 8Canada’s Michael Smith Genome Sciences Centre, Vancouver, BC V5Z4S6, Canada. 9Vancouver Prostate Centre, Vancouver, BC V6H3Z6, Canada. 10Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z1L3, Canada. 11BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada. 12Seattle Children's Research Institute, Seattle, WA 98101, USA. 13Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T1Z4, Canada. #These authors contributed equally. *Correspondence: Poul H Sorensen. Mailing address: 675 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. Email: [email protected]. Tel. (604) 675-8202. Running Title: IL1RAP is a promising surface target in Ewing sarcoma Keywords: Ewing sarcoma, anoikis, metastasis, cysteine metabolism, redox homeostasis Conflict of Interest: This study was funded by National Institutes of Health (NIH) U54 Pediatric Immunotherapy Discovery and Development Network (1U54CA232568-01), a St. Baldrick’s Foundation/American Association for Cancer Research/Stand Up to Cancer Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT-27-17), and a St. Baldrick's Foundation/Martha's Better Ewing Sarcoma Treatment (BEST) Grant (#663113). H.F.Z. is funded by a fellowship from the Canadian Institutes of Health Research (#415377) and a trainee award from the Michael Smith Foundation for Health Research partnered with the Lotte and John Hecht Memorial Foundation (#18569). Patent associated with this study has been submitted (PCT Application No.: PCT/US2021/026727). All other authors declare no conflict of interest. 1 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 21, 2021; DOI: 10.1158/2159-8290.CD-20-1690 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Cancer cells must overcome anoikis (detachment-induced death) to successfully metastasize. Using proteomic screens, we found that distinct oncoproteins upregulate IL-1 receptor accessory protein (IL1RAP) to suppress anoikis. IL1RAP is directly induced by oncogenic fusions of Ewing sarcoma (EwS), a highly metastatic childhood sarcoma. IL1RAP inactivation triggers anoikis and impedes metastatic - dissemination of EwS 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 EwS cells. Therefore, we define IL1RAP as a new cell surface target in EwS, 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. 2 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 21, 2021; DOI: 10.1158/2159-8290.CD-20-1690 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Metastasis is responsible for up to 90% of cancer deaths, representing the leading cause of cancer- associated mortality1. Despite extensive research into this process, reducing metastasis-associated mortality remains a major clinical unmet need2, and identification of key drivers of metastasis carries paramount significance. Ewing sarcoma (EwS) is the second most common bone cancer in children and adolescents, and metastatic status at diagnosis remains the strongest prognostic factor across various standard-of-care treatments3. EwS patients with metastatic disease have a <30% overall survival rate, which has not improved for decades3. In the metastatic cascade, a major obstacle that disseminated tumour cells must overcome is anoikis4, or cell death induced by loss of attachment to the extracellular matrix (ECM). Genes that promote resistance to anoikis can confer enhanced metastatic capacity4-5. Delineation of novel anoikis resistance factors will open new avenues for designing effective therapies to block metastasis. However, most in vitro studies have historically used conventional 2-dimentional (2D) cultures to identify regulators of cancer growth6-8, hindering the identification of important anoikis regulators. Therefore in this study we utilized 3D cultures of tumor cells to model anoikis stress9 as a means to identify novel anti-anoikis and pro-metastatic signatures. The tripeptide metabolite, glutathione (GSH), is a key antioxidant in mammalian cells, and its availability represents a major determinant of cellular redox homeostasis10-11. GSH depletion results in accumulation of reactive oxygen species (ROS) as well as oxidized membrane phospholipids (known as lipid ROS), which may induce cell death, including anoikis4,12-13 and ferroptosis (i.e. iron-dependent cell death)14-16. The rate-limiting substrate for GSH synthesis is cysteine, which cells acquire from exogenous cystine - uptake via the xCT/CD98 transporter (also known as system Xc ), or de novo synthesis via the transsulfuration (TSS) pathway that converts serine and methionine to cysteine10,11,17,18. Upon extracellular cystine depletion or xCT blockade, cells can switch to the TSS pathway to maintain cysteine pools and cell survival18. Despite the critical role of cysteine for metabolic and redox homeostasis in cancer cells10-11, how these two processes are balanced to meet the high demand for cysteine remains elusive, such as in cancer cells with low expression of xCT19-20 or of key enzymes for TSS such as Cystathionine β-Synthase (CBS)18. A better understanding of specific factors that mediate the interplay between cystine uptake and the TSS for cysteine replenishment may elucidate novel approaches to block cysteine metabolism and therefore ROS homeostasis in cancer cells. In this report, we utilized combined proteomic and translatomic screens in 3D cultures to identify factors that mitigate anoikis in fibroblasts transformed by distinct oncoproteins. This approach identified IL1RAP as a previously unknown suppressor of anoikis and an important regulator of redox homeostasis in transformed cells. IL1RAP is a cell surface protein known to associate with IL-1 receptors (IL1Rs), functioning as an IL1R co-receptor to mediate IL-1 family cytokine signaling pathways in immune cells, e.g. T lymphocytes and mast cells21. IL1RAP was previously shown to have pro-tumorigenic roles in myeloid leukemias22-25, while its role in other cancers is unknown. Instead, we found that in Ewing sarcoma (EwS), a highly metastatic childhood sarcoma, EWS-FLI1 and EWS-ERG fusion oncoproteins - characteristic of this malignancy directly induce IL1RAP expression to activate both the system Xc 3 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 21, 2021; DOI: 10.1158/2159-8290.CD-20-1690 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. transporter and the TSS pathway, but independently from IL1R. This unexpected function of IL1RAP confers EwS cells with the ability to maintain and replenish cysteine and GSH pools even when extracellular cystine uptake is limited, which is exploited as a cytoprotective mechanism during the metastatic
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