Modeling high-risk Wilms tumors enables the discovery of therapeutic vulnerability

作者：Gui Ma, Ang Gao, Jiani Chen, Peng Fei Liu, Rakesh Sarda, Jessica Gulliver, Yidan Wang, Carstyn Joiner, Mingshan Hu, Eui-Jun Kim, Herman Yeger, Hau D. Le, Xiang Chen, Wan‐Ju Li, Wei Xu · 发表于：Cell Reports Medicine · 年份：2024 · DOI：10.1016/j.xcrm.2024.101770 · 被引用次数：8 · 研究领域：Renal and related cancers、Pluripotent Stem Cells Research、Ethics and Legal Issues in Pediatric Healthcare

Wilms tumor (WT) is the most common pediatric kidney cancer treated with standard chemotherapy. However, less-differentiated blastemal type of WT often relapses. To model the high-risk WT for therapeutic intervention, we introduce pluripotency factors into WiT49, a mixed-type WT cell line, to generate partially reprogrammed cells, namely WiT49-PRCs. When implanted into the kidney capsule in mice, WiT49-PRCs form kidney tumors and develop both liver and lung metastases, whereas WiT49 tumors do not metastasize. Histological characterization and gene expression signatures demonstrate that WiT49-PRCs recapitulate blastemal-predominant WTs. Moreover, drug screening in isogeneic WiT49 and WiT49-PRCs leads to the identification of epithelial- or blastemal-predominant WT-sensitive drugs, whose selectivity is validated in patient-derived xenografts (PDXs). Histone deacetylase (HDAC) inhibitors (e.g., panobinostat and romidepsin) are found universally effective across different WT and more potent than doxorubicin in PDXs. Taken together, WiT49-PRCs serve as a blastemal-predominant WT model for therapeutic intervention to treat patients with high-risk WT. • Partially reprogrammed WiT49 cells develop both liver and lung metastases • Partially reprogrammed WiT49 cells recapitulate blastema-predominant Wilms tumors • WiT49 and partially reprogrammed WiT49 cells are suitable for drug screening • HDAC inhibitors are effective against epithelial and blastemal Wilms tumors Ma et al. generate a...