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

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

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 4

Wt1 loss leads to subtle alteration of gene expression in Kras-transformed MEFs.

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Wt1 loss leads to subtle alteration of gene expression in Kras-transfor...
(A) Heat map of gene expression analysis of KrasG12D/+ and KrasG12D/+;Wt1Δ/Δ MEFs compared with wild-type and Wt1Δ/Δ MEFs. Gene sets with at least a 2-fold change and an FDR of less than 0.1 for comparison between any of the 4 genotypes are shown. Enrichment plots of (B) MSigDB gene sets of glutamine metabolism genes as well as experimentally derived gene sets downregulated by glutamate or leucine starvation and (C) MSigDB gene sets for Myc pathway genes. (D) Heat map of differentially expressed genes between KrasG12D/+ and KrasG12D/+;Wt1Δ/Δ MEFs as determined by PAM analysis. (E) A large gene expression compendium of human lung cancer gene expression (heat map) was analyzed in order to identify patients with either high expression or low expression of Kras signature genes. After training with KrasG12D/+;Wt1Δ/Δ versus KrasG12D/+ MEF data, high WT1 and low WT1 gene signature samples were identified from within the human lung carcinoma “KRAS signature high” and “KRAS signature low” groups. Kaplan-Meier analysis was used to assess survival of lung cancer patients with either high or low KRAS gene expression signatures as a function of the high/low WT1 gene signature. Log-rank P values indicate differences between the 2 groups.