Discovery and characterization of exceptionally specific surface oncoprotein LIPI in Ewing Sarcoma

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Project Summary Children and young adults with metastatic Ewing sarcoma driven by oncogenic fusion transcription factor EWS- FLI1 continue to have poor outcomes. Immunotherapies using T cells, NK cells, cancer vaccines, and monoclonal antibodies are being considered for Ewing sarcoma, especially for recurrent patients. The identification of human tumor-associated antigens (TAAs) recognized by the immune system is crucial for immunotherapy. Through integration of Ewing sarcoma cell line gene expression, ChIP-seq, and normal and cancer tissue gene expression from the Genotype-Tissue Expression (GTEx), and the TCGA project, we have identified LIPI as a highly specific tumor antigen and a potential oncogene that relies on the transcriptional activity of EWS-FLI1 in Ewing sarcoma. LIPI (Lipase member I (EC:3.1.1.-) is an evolutionarily conserved protein predicted to poses a transmembrane domain and extracellular lipid hydrolase domain. The biological function of LIPI is not known but the enzymatic activity of LIPI is expected to produce lysophosphatidic acid (LPA) that potently affects several biological functions including proliferation, cell survival, and metastasis of tumor cells. We hypothesize that the LIPI is a unique biomarker and an oncogene that is expressed exclusively in Ewing sarcoma and is a potential target for cell based therapy. To our knowledge, this proposal represents the first study evaluating the role of LIPI in cellular physiology and in particular Ewing sarcoma progression and metastasis. The two specific aims of the projects are: Specific Aim 1: To elucidate the regulation and role of cell surface LIPI in Ewing sarcoma Specific Aim 2: To investigate the role of LIPI in Ewing sarcoma growth/metastasis. Following the successful completion of the proposed aims in this application, we will have evaluated the potential of LIPI as a Ewing sarcoma specific surface oncoprotein, and will have a long-term impact by establishing the strong foundation for the development of LIPI-directed immunotherapeutics against Ewing sarcoma.