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Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models
Silvestre Vicent, … , William C. Hahn, E. Alejandro Sweet-Cordero
Silvestre Vicent, … , William C. Hahn, E. Alejandro Sweet-Cordero
Published October 25, 2010
Citation Information: J Clin Invest. 2010;120(11):3940-3952. https://doi.org/10.1172/JCI44165.
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Research Article Article has an altmetric score of 8

Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models

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Abstract

KRAS is one of the most frequently mutated human oncogenes. In some settings, oncogenic KRAS can trigger cellular senescence, whereas in others it produces hyperproliferation. Elucidating the mechanisms regulating these 2 drastically distinct outcomes would help identify novel therapeutic approaches in RAS-driven cancers. Using a combination of functional genomics and mouse genetics, we identified a role for the transcription factor Wilms tumor 1 (WT1) as a critical regulator of senescence and proliferation downstream of oncogenic KRAS signaling. Deletion or suppression of Wt1 led to senescence of mouse primary cells expressing physiological levels of oncogenic Kras but had no effect on wild-type cells, and Wt1 loss decreased tumor burden in a mouse model of Kras-driven lung cancer. In human lung cancer cell lines dependent on oncogenic KRAS, WT1 loss decreased proliferation and induced senescence. Furthermore, WT1 inactivation defined a gene expression signature that was prognostic of survival only in lung cancer patients exhibiting evidence of oncogenic KRAS activation. These findings reveal an unexpected role for WT1 as a key regulator of the genetic network of oncogenic KRAS and provide important insight into the mechanisms that regulate proliferation or senescence in response to oncogenic signals.

Authors

Silvestre Vicent, Ron Chen, Leanne C. Sayles, Chenwei Lin, Randal G. Walker, Anna K. Gillespie, Aravind Subramanian, Gregory Hinkle, Xiaoping Yang, Sakina Saif, David E. Root, Vicki Huff, William C. Hahn, E. Alejandro Sweet-Cordero

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Figure 2

Identification of Wt1 loss as a Kras-specific synthetic-lethal interaction in MEFs.

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Identification of Wt1 loss as a Kras-specific synthetic-lethal interacti...
(A) Design of MEFs validation screen. MEFs were first infected with AdCre followed by infection with lentiviral vectors containing pools of shRNAs. 5 independent MEF lines of each genotype were assessed with each shRNA pool. The colored bars represent the relative ratio of the MFI of a particular barcode corresponding to a shRNA at T1, T2, or T3 over T0. The light blue bar depicts a theoretical barcode that is negatively selected. (B) Rac1, Phb2, and Wt1 are negatively selected in KrasLSL-G12D/+ MEFs. Box plots indicate mean ± SD of log2 of the MFI fold change for each gene comparing T1 versus T0. P values were obtained using a 2-tailed t test. (C) Wt1 shRNAs are not negatively selected in transformed lung epithelial cell lines expressing wild-type Kras. MLE12 cells were infected with the same shRNA pools used for the MEF experiments. log2 of the MFI fold change in the presence of 2 Wt1 shRNAs after 3 weeks of proliferation in vitro was measured and compared with the results for LKR10 and LKR13. Error bars show mean ± SD. (D) LKR13 cells were infected with shRNAs to GFP (control), Kras, and Wt1, selected for 3 days, and injected subcutaneously (n = 8) into Balb/cnu/nu mice. Results show tumor volume at final day of experiment (day 24 after injection). Representative tumors are shown. Error bars indicate mean ± SEM. All P values are for a 2-tailed t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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