Retinoblastoma from human stem cell-derived retinal organoids

Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. Children with germline mutations in RB1 have a high likelihood of developing retinoblastoma and other malignancies later in life. Genetically engineered mouse models of retinobla...

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Published in:Nature communications Vol. 12; no. 1; pp. 4535 - 13
Main Authors: Norrie, Jackie L., Nityanandam, Anjana, Lai, Karen, Chen, Xiang, Wilson, Matthew, Stewart, Elizabeth, Griffiths, Lyra, Jin, Hongjian, Wu, Gang, Orr, Brent, Tran, Quynh, Allen, Sariah, Reilly, Colleen, Zhou, Xin, Zhang, Jiakun, Newman, Kyle, Johnson, Dianna, Brennan, Rachel, Dyer, Michael A.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 27.07.2021
Nature Publishing Group
Nature Portfolio
Subjects:
13/51
38/23
38/88
38/91
45/100
631/532/2064/2158
631/67/2332
Animal models
Cancer
Cell culture
Children
Culture
Deactivation
Differentiation (biology)
Eye (anatomy)
Genetic engineering
Humanities and Social Sciences
Inactivation
multidisciplinary
Mutation
Organoids
Patients
Pediatrics
Pluripotency
Retina
Retinoblastoma
Retinoblastoma protein
Science
Science (multidisciplinary)
Stem cell transplantation
Stem cells
Tumorigenesis
Tumors
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. Children with germline mutations in RB1 have a high likelihood of developing retinoblastoma and other malignancies later in life. Genetically engineered mouse models of retinoblastoma share some similarities with human retinoblastoma but there are differences in their cellular differentiation. To develop a laboratory model of human retinoblastoma formation, we make induced pluripotent stem cells (iPSCs) from 15 participants with germline RB1 mutations. Each of the stem cell lines is validated, characterized and then differentiated into retina using a 3-dimensional organoid culture system. After 45 days in culture, the retinal organoids are dissociated and injected into the vitreous of eyes of immunocompromised mice to support retinoblastoma tumor growth. Retinoblastomas formed from retinal organoids made from patient-derived iPSCs have molecular, cellular and genomic features indistinguishable from human retinoblastomas. This model of human cancer based on patient-derived iPSCs with germline cancer predisposing mutations provides valuable insights into the cellular origins of this debilitating childhood disease as well as the mechanism of tumorigenesis following RB1 gene inactivation. Retinoblastoma is a heritable pediatric cancer driven by mutations in RB1. Here, the authors demonstrate the first patient derived model of retinoblastoma using iPSCs from patients with germline mutations in RB1.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-24781-7