title: Modeling Developmental and Tumorigenic Aspects of Trilateral Retinoblastoma via Human Embryonic Stem Cells.
abstract: Human embryonic stem cells (hESCs) provide a platform for studying human development and understanding mechanisms underlying diseases. Retinoblastoma-1 (RB1) is a key regulator of cell cycling, of which biallelic inactivation initiates retinoblastoma, the most common congenital intraocular malignancy. We developed a model to study the role of RB1 in early development and tumor formation by generating RB1-null hESCs using CRISPR/Cas9. RB1-/-hESCs initiated extremely large teratomas, with neural expansions similar to those of trilateral retinoblastoma tumors, in which retinoblastoma is accompanied by intracranial neural tumors. Teratoma analysis further revealed a role for the transcription factor ZEB1 in RB1-mediated ectoderm differentiation. Furthermore, RB1-/-cells displayed mitochondrial dysfunction similar to poorly differentiated retinoblastomas. Screening more than 100 chemotherapies revealed an RB1-/--specific cell sensitivity to carboplatin, exploiting their mitochondrial dysfunction. Together, our work provides a human pluripotent cell model for retinoblastoma and sheds light on developmental and tumorigenic roles of RB1.
authors.affiliation: The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat-Ram, Jerusalem 91904, Israel.
authors.forename: Yishai
authors.initials: Y
authors.lastname: Avior
authors.affiliation: The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat-Ram, Jerusalem 91904, Israel.
authors.forename: Elyad
authors.initials: E
authors.lastname: Lezmi
authors.affiliation: The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat-Ram, Jerusalem 91904, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Yanuka
authors.affiliation: The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat-Ram, Jerusalem 91904, Israel. Electronic address: nissimb@mail.huji.ac.il.
authors.forename: Nissim
authors.initials: N
authors.lastname: Benvenisty
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064113:CRISPR-Cas Systems; D016190:Carboplatin / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D019572:Retinal Neoplasms / Q000378:metabolism / Q000473:pathology*; D012175:Retinoblastoma / Q000378:metabolism / Q000473:pathology*; D056286:Retinoblastoma Binding Proteins / Q000235:genetics / Q000378:metabolism; D013724:Teratoma / Q000378:metabolism / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D016190:Carboplatin; D044767:Ubiquitin-Protein Ligases
keywords: RB1; ZEB1; disease modeling; human embryonic stem cells; trilateral retinoblastoma