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

Silvestre Vicent1, Ron Chen, Leanne C Sayles

  • 1Cancer Biology Program, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.

The Journal of Clinical Investigation
|October 26, 2010
PubMed

Insights

Wilms tumor 1 (WT1) acts as a key regulator for oncogenic KRAS signaling, determining whether cells senesce or proliferate. WT1 loss induces senescence and reduces tumor growth in Kras-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS mutations are common in human cancers, leading to either cellular senescence or hyperproliferation.
  • Understanding the mechanisms behind these distinct outcomes is crucial for developing targeted therapies for RAS-driven cancers.

Purpose of the Study:

  • To identify critical regulators of senescence and proliferation downstream of oncogenic KRAS signaling.
  • To investigate the role of Wilms tumor 1 (WT1) in regulating cellular responses to oncogenic KRAS.

Main Methods:

  • Functional genomics and mouse genetics were employed.
  • Experiments involved mouse primary cells and human lung cancer cell lines with oncogenic KRAS.
  • Analysis included gene expression profiling and tumor burden assessment in mouse models.

Main Results:

  • WT1 suppression induced senescence in mouse cells with oncogenic Kras but not in wild-type cells.
  • Loss of WT1 reduced tumor burden in a Kras-driven lung cancer mouse model.
  • In human lung cancer cells, WT1 loss decreased proliferation and induced senescence, correlating with survival in KRAS-activated patients.

Conclusions:

  • WT1 is identified as a critical regulator of oncogenic KRAS signaling, dictating senescence or proliferation.
  • WT1 inactivation reveals a prognostic gene expression signature in KRAS-mutated lung cancers.
  • These findings offer insights into therapeutic strategies for RAS-driven cancers by targeting the WT1 network.

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