Modeling high-risk blastemal and metastatic Wilms tumors by reprogramming WiT49 cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246479 | GEO | 2024/11/06

REPOSITORIES: GEO