Profil N° (à remplir par VAS) FINANCEMENT Demandé Acquis Fiche Résumé du sujet de thèse 2017 Champs disciplinaire Autres et Autres Titre de la thèse : (1-2 lignes) Identification and characterization of Iqub, a new Cancer/Testis (CT) gene. 3 mots-clés : (1 ligne) CT antigen / spermatogenesis / immunotherapy ACRONYME CANTES Unité/équipe encadrante : Inserm U1085 IRSET, group REMEDE Nom du responsable scientifique Soazik Jamin nom du codirecteur le cas échéant : Michael Primig Contact : [email protected] Contexte socioéconomique et scientifique : (10 lignes) The death rate of cancer remains high in spite of the development of numerous therapies. Approaches based on immunotherapy are beginning to replace or complement chemotherapy. The identification of novel target proteins is therefore an essential step for these new promising treatments. We propose to study IQUB, a new Cancer/Testis gene (CT gene). These genes are a key element of methods that involve a patient’s immune system. IQUB is de-repressed in in all somatic cancers that we analyzed using GeneChip expression data from a very large cancer study published by a US consortium. Moreover, mutations in IQUB have been associated with gastric cancer. This makes the gene an interesting candidate for the development of novel immunotherapies. Analysis of a transgenic mouse model should reveal the molecular mechanism and the signaling pathway involved in its potential role as an oncogene. Little is known about IQUB but protein interaction data point to several functions and possible association with a member of the CT gene founding protein MAGE. Les hypothèses et questions posées (8 lignes) We hypothesize that understanding IQUB’s essential role in meiosis and gametogenesis will help uncover its proposed mechanism of action during somatic cancer progression. It is therefore essential to first understand IQUB’s role in germ cell interaction and differentiation before determining its possible function in somatic cancer development. IQUB was deleted in a mouse model by KOMP (Knockout Mouse Project) and the transgenic animals are available for further analysis. The homozygote males are infertile (published in the database of the International Mouse Phenotyping Consortium IMPC, www.impc.org). However, the phenotype is not understood at the histological and molecular level and the functions of IQUB remain unknown. Les grandes étapes de la thèse et démarche (10-12 lignes) The project will be done along three axes. First, the target gene expression profile will be determined at the level of RNA and protein on testicular sections and TMAs (Tissue MicroArrays) of different cancers in comparison to their corresponding healthy tissues. Then the mouse phenotype will be analyzed to ask how spermatogenesis in altered and which step is affected. Different marker proteins will be studied. IQUB is probably involved in cell-cell interactions via cilia in the germline. Interaction data suggest IQUB to be a hub protein that binds different regulatory proteins and known CT genes. Finally, we will use different in vitro cell lines to study the protein’s role in cell division and differentiation to help assess its value as a target for immunotherapy. Approches méthodologiques et techniques envisagées (4-6 lignes) The student will employ molecular biological (PCR, in situ hybridization, cloning), biochemical (immunohistochemistry and immunofluorescence) and cell biological (transfection) methods. Compétences scientifiques et techniques requises par le candidat (2 lignes) This project requires training in molecular biology and/or biochemistry.