Retinoblastoma from human stem cell-derived retinal organoids

Jackie L. Norrie, Anjana Nityanandam, Karen Lai, Xiang Chen, Matthew Wilson, Elizabeth Stewart, Lyra Griffiths, Hongjian Jin, Gang Wu, Brent Orr, Quynh Tran, Sariah Allen, Colleen Reilly, Xin Zhou, Jiakun Zhang, Kyle Newman, Dianna Johnson, Rachel Brennan () and Michael A. Dyer ()
Additional contact information
Jackie L. Norrie: St. Jude Children’s Research Hospital
Anjana Nityanandam: St. Jude Children’s Research Hospital
Karen Lai: St. Jude Children’s Research Hospital
Xiang Chen: St. Jude Children’s Research Hospital
Matthew Wilson: University of Tennessee Health Science Center
Elizabeth Stewart: St. Jude Children’s Research Hospital
Lyra Griffiths: St. Jude Children’s Research Hospital
Hongjian Jin: St. Jude Children’s Research Hospital
Gang Wu: St. Jude Children’s Research Hospital
Brent Orr: St. Jude Children’s Research Hospital
Quynh Tran: St. Jude Children’s Research Hospital
Sariah Allen: St. Jude Children’s Research Hospital
Colleen Reilly: St. Jude Children’s Research Hospital
Xin Zhou: St. Jude Children’s Research Hospital
Jiakun Zhang: St. Jude Children’s Research Hospital
Kyle Newman: St. Jude Children’s Research Hospital
Dianna Johnson: University of Tennessee Health Science Center
Rachel Brennan: St. Jude Children’s Research Hospital
Michael A. Dyer: St. Jude Children’s Research Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24781-7

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