Modeling high-risk blastemal and metastatic Wilms tumors by reprogramming WiT49 cells
Wilms' tumor (WT) is the most common pediatric kidney cancer with more than a 90% overall survival rate in response to standard chemotherapy. However, less-differentiated blastemal type of WT often metastasize and relapse. To remodel the high-risk WT for therapeutic intervention, we partially reprogrammed WIT49, a mixed type of WT cell line, to iPSCs, which we termed as WiT49-PRCs (Partial reprogrammed iPSCs). WiT49-PRCs express stem cell markers. When implanted into the kidney capsule in mice, WiT49-PRCs formed kidney tumors and developed both liver and lung metastases, whereas WiT49 tumors do not metastasize. Histological characterization and gene expression signatures demonstrated that WiT49-PRC recapitulates blastema-dominant WTs. Moreover, screening FDA-approved drugs in isogeneic WiT49 and WiT49-PRC cells led to the identification of epithelial- or blastemal-dominant WT-sensitive drugs. A subset of drugs was discovered with selectivity towards blastemal WT patient derived xenografts (PDXs).  HDAC inhibitors (e.g. panobinostat and romedipsin) were found universally effective across different WT and more potent than doxorubicin in PDXs. Taken together, WiT49-PRC serves as a blastemal-dominant WT model for therapeutic intervention to improve the treatment of high-risk WT patients. Overall design: Wilms tumor cell line, WiT49 was partially reprogrammed into iPSC by transfecting the cells with episomal vectors. Real-time quantitative PCR was used to test the expression level of stem cell markers of the partial reprogrammed WiT49 cells (PRCs) and Parental cells. Orthotopic xenograft was performed to detect tumor growth and metastasis to the liver and lung. HE staining and RNA-seq was applied to determine the histology and gene expression signatures of WiT49-Parental and WiT49-PRCs. The histology and gene signatures of WiT49-Parental and WiT49-PRCs were compared with Wilms tumor patient and PDX samples. Drug screening was performed by using WiT49-Parental and WiT49-PRC models. Selected drugs including HDAC inhibitors were tested in epithelial and blastemal Wilms tumor PDX models.