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.

WT1 in disease: shifting the epithelial–mesenchymal balance

“…This, however, remains to be validated experimentally. Finally, recent data support a role for WT1 in overcoming senescence downstream of oncogenically activated RAS [51]. Previously, the same has been shown for activation of an EMT via expression of Twist [52], so this finding provides another way in which a WT1-controlled EMT could be advantageous for a developing tumour.…”

Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells

“…However, dissecting the downstream genetic dependencies that constitute Ras addiction has proved more complex. Several genome-wide screens against the KRAS oncogene have identified a surprisingly diverse set of genes whose depletion causes greater toxicity in KRAS mutant cells compared with KRAS WT cells (6,(35)(36)(37)(38)(39). We think that this finding reflects a broad dependency of Ras mutant cells on various stress relief pathways that constitute what we termed nononcogene addictions (7).…”

Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia

“…8,9 In lung cancer, Wt1 has been shown to play a role in murine lung cancer models driven by Kras mutations where deletion or suppression of Wt1 resulted in senescence of primary murine cells expressing Kras, but had no effect on wild type cells. 10 Furthermore, loss of Wt1 led to decreased proliferation and tumor burden in Kras-driven lung carcinoma, © Ferrata Storti Foundation thus implicating Wt1 as a necessary component of Krasdriven oncogenesis. Taken together, these observations indicate that a spectrum of mutations in WT1 can lead to both inherited developmental syndromes and cancer predisposition.…”