KRAS is one of the most frequently mutated human oncogenes. In some settings oncogenic KRAS can trigger cellular senescence, whereas in others expression leads to hyperproliferation. Given the importance of KRAS mutation in human cancer, elucidating the mechanisms regulating these two drastically distinct outcomes would help identify novel therapeutic approaches in RAS-driven cancers. We have identified a novel role for Wilms tumor-1 (WT1) as a critical regulator of senescence and proliferation downstream of oncogenic KRAS. Loss of Wt1 leads to senescence in mouse primary cells and human tumor cells in an oncogenic KRAS- dependent manner. In addition, WT1 expression is specifically upregulated in chemoresistant tumor cells in a mouse model of lung cancer. These findings reveal an unexpected role for WT1 as a key regulator of the genetic network downstream of KRAS and suggest a key role for Wt1 in chemoresistance. In this proposal, we will use a combination of molecular, genetic and biochemical approaches to elucidate the mechanistic basis for the observed interaction between oncogenic KRAS and WT1. Preliminary data suggests that at least part of the role of WT1 is mediated by post-transcriptional regulation of RNAs. Thus, this proposal will use state-of- the-art approaches to analyze the role of Wt1 on splicing and protein translation. In addition, we will determine the role of WT1 in regulating chemotherapy resistance in KRAS-driven lung tumors.

Public Health Relevance

KRAS is one of the most frequently mutated oncogenes in human cancer. However, the reason why KRAS mutation leads to cancer in some contexts (tissues) but not in others is not completely understood. We have identified a novel connection between the ability of KRAS to cause cells to proliferate and the expression of Wilm's tumor-1 (WT1). This proposal will focus on understanding the mechanisms and consequences of this interaction for tumor initiation, senescence and chemotherapy response.

National Institute of Health (NIH)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Watson, Joanna M
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Stanford University
Schools of Medicine
United States
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