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

Autor:	Ma G; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Gao A; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Chen J; Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA., Liu P; 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., Sarda R; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA., Gulliver J; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA., Wang Y; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Joiner C; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Hu M; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Kim EJ; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Yeger H; Program in Developmental and Stem Cell Biology, Peter Gilgan Centre for Research and Learning, SickKids, Toronto, ON M5G 0A4, Canada., Le HD; Department of Surgery, Division of Pediatric Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA., Chen X; Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA., Li WJ; Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, WI, USA., Xu W; 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.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Oct 15; Vol. 5 (10), pp. 101770. Date of Electronic Publication: 2024 Oct 04.
DOI:	10.1016/j.xcrm.2024.101770
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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