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Stem Cell Reports. 2017 May 9;8(5):1354-1365. doi: 10.1016/j.stemcr.2017.03.005. Epub 2017 Apr 6.

Modeling Developmental and Tumorigenic Aspects of Trilateral Retinoblastoma via Human Embryonic Stem Cells.

Author information

1
The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat-Ram, Jerusalem 91904, Israel.
2
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.

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.

KEYWORDS:

RB1; ZEB1; disease modeling; human embryonic stem cells; trilateral retinoblastoma

PMID:
28392220
PMCID:
PMC5425613
DOI:
10.1016/j.stemcr.2017.03.005
[Indexed for MEDLINE]
Free PMC Article

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