Human embryonic stem cell-derived organoidal retinoblastoma reveals cancerous origin and therapeutic target

Retinoblastoma (Rb) is the most prevalent intraocular malignant tumor in children with less than 30% survival rate globally. Rb genetic predisposition has been well defined for decades, whereas its developmental origin and drug agents remain largely unexplored. Here we developed the first organoidal retinoblastoma model derived from human embryonic stem cells (hESCs) with a biallelic knockout (RB1-/-) or mutagenesis (RB1Mut/Mut) of the RB1 gene, which exhibit extreme consistent properties of Rb tumorigenesis, transcriptome, and genome-wide methylation. Using single-cell RNA-seq and immunostaining of this model, we found that developmentally Rb originated from ARR3+ maturing cone precursors and a new cell type of unfolded protein response occurred in the organoidal retinoblastoma. A key PI3K-Akt pathway was aberrantly regulated, and its strong activator SYK (encoding proto-oncogenic spleen tyrosine kinase) was significantly upregulated in the cancerous organoids. Furthermore, we demonstrated that the SYK inhibitors, A502 and B502, have more significant therapeutic response on the early-stage organoidal retinoblastoma compared to four well-established chemotherapeutic drugs in clinic. Collectively, we established a brand-new organoidal retinoblastoma model derived from human ESCs in-a-dish and discovered its cell-of-origin and potential drug agents, shedding light on development and therapeutics of human cancers.