Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin.

Retinoblastoma (Rb) is the most prevalent intraocular malignancy in children, with a worldwide survival rate <30%. We have developed a cancerous model of Rb in retinal organoids derived from genetically engineered human embryonic stem cells (hESCs) with a biallelic mutagenesis of the RB1 gene. These organoid Rbs exhibit properties highly consistent with Rb tumorigenesis, transcriptome, and genome-wide methylation. Single-cell sequencing analysis suggests that Rb originated from ARR3-positive maturing cone precursors during development, which was further validated by immunostaining. Notably, we found that the PI3K-Akt pathway was aberrantly deregulated and its activator spleen tyrosine kinase (SYK) was significantly up-regulated. In addition, SYK inhibitors led to remarkable cell apoptosis in cancerous organoids. In conclusion, we have established an organoid Rb model derived from genetically engineered hESCs in a dish that has enabled us to trace the cell of origin and to test novel candidate therapeutic agents for human Rb, shedding light on the development and therapeutics of other malignancies. Copyright © 2020 the Author(s). Published by PNAS.

Citation

Hui Liu, Yan Zhang, You-You Zhang, Yan-Ping Li, Zi-Qi Hua, Chang-Jun Zhang, Kun-Chao Wu, Fulong Yu, Yaru Zhang, Jianzhong Su, Zi-Bing Jin. Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin. Proceedings of the National Academy of Sciences of the United States of America. 2020 Dec 29;117(52):33628-33638

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PMID: 33318192

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