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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129562-04
Application #
8512665
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
2007-07-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$254,137
Indirect Cost
$98,097
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Gwinn, Dana M; Lee, Alex G; Briones-Martin-Del-Campo, Marcela et al. (2018) Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase. Cancer Cell 33:91-107.e6
Vallejo, Adrian; Perurena, Naiara; Guruceaga, Elisabet et al. (2017) An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer. Nat Commun 8:14294