Abstract
Retinoblastoma (Rb) is the most prevalent intraocular malignant tumour in children with survival rate less than 30% globally. Its developmental origin and drug agents remain largely unexplored. Here, we developed the first organoid Rb model derived from human embryonic stem cells (hESCs) with a biallelic knockout (RB1-/-) or mutagenesis (RB1Mut/Mut). These organoid retinoblastomas exhibit extremely consistent properties of Rb tumourigenesis, transcriptome, and genome-wide methylation. We found Rb originated from ARR3+ maturing cone precursors during development and a new unfolded protein response cell type. A key PI3K-Akt pathway was aberrantly regulated, and its activator SYK was significantly upregulated. Furthermore, the SYK inhibitors induced a more significant therapeutic response from early-stage organoid Rb. In conclusion, we established a novel organoid Rb model derived from human ESCs in a dish and discovered its cell-of-origin and potential drug agents, thus shedding light on the development and therapeutics of other human cancers.
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