Cancer Institute A national cancer institute
designated cancer center

Alejandro Sweet-Cordero

Publication Details

  • Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models JOURNAL OF CLINICAL INVESTIGATION Vicent, S., Chen, R., Sayles, L. C., Lin, C., Walker, R. G., Gillespie, A. K., Subramanian, A., Hinkle, G., Yang, X., Saif, S., Root, D. E., Huff, V., Hahn, W. C., Sweet-Cordero, E. A. 2010; 120 (11): 3940-3952


    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.

    View details for DOI 10.1172/JCI44165

    View details for Web of Science ID 000283621800028

    View details for PubMedID 20972333

Stanford Medicine Resources:

Footer Links: