2. Academic Validation
  3. Modeling high-risk Wilms tumors enables the discovery of therapeutic vulnerability

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

  • Cell Rep Med. 2024 Oct 15;5(10):101770. doi: 10.1016/j.xcrm.2024.101770.
Gui Ma 1,  Ang Gao 1,  Jiani Chen 2,  Peng Liu 3,  Rakesh Sarda 4,  Jessica Gulliver 4,  Yidan Wang 1,  Carstyn Joiner 1,  Mingshan Hu 1,  Eui-Jun Kim 1,  Herman Yeger 5,  Hau D Le 6,  Xiang Chen 2,  Wan-Ju Li 7,  Wei Xu 8
Affiliations

Affiliations

  • 1 McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA.
  • 2 Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
  • 3 Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA.
  • 4 Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA.
  • 5 Program in Developmental and Stem Cell Biology, Peter Gilgan Centre for Research and Learning, SickKids, Toronto, ON M5G 0A4, Canada.
  • 6 Department of Surgery, Division of Pediatric Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 7 Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, WI, USA.
  • 8 McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA. Electronic address: wxu@oncology.wisc.edu.
PMID: 39368485 DOI: 10.1016/j.xcrm.2024.101770
Abstract

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.

Keywords

HDAC inhibitors; Panobinostat; Romedipsin; WIT49; Wilms tumor model; iPSC.

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