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Rac1-Mediated DNA Damage and Inflammation Promote Nf2 Tumorigenesis but Also Limit Cell-Cycle Progression

Yuhao Shi1, Saumya R Bollam1, Shannon M White1

  • 1Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.

Developmental Cell
|November 8, 2016
PubMed

Insights

Neurofibromatosis type 2 (NF2) tumor suppressor Merlin regulates Hippo-Yap and Rac1-Pak1 pathways. Co-deletion of Rac1 with Nf2 blocks tumor initiation but worsens liver enlargement, suggesting Rac1 acts as an inflammation switch.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Merlin, encoded by the Nf2 gene, is a tumor suppressor.
  • Merlin regulates the Hippo-Yap and Rac1-Pak1 pathways.
  • NF2 mutations are implicated in various cancers.

Purpose of the Study:

  • Investigate the roles of Rac1 and Yap in Nf2-deficient liver tumorigenesis.
  • Elucidate the mechanisms by which Rac1 influences tumor initiation and progression.
  • Determine the relationship between senescence and NF2 tumor phenotypes.

Main Methods:

  • Genetically engineered murine liver models with Nf2 and Rac1 co-deletion.
  • Analysis of tumor initiation, hepatomegaly, and molecular signaling pathways.
  • Assessment of reactive oxygen species, inflammatory markers, and cell cycle regulators.

Main Results:

  • Co-deletion of Rac1 and Nf2 blocked tumor initiation but exacerbated hepatomegaly.
  • Yap drives proliferation in Nf2 tumorigenesis; Rac1 acts as an inflammation switch via reactive oxygen species.
  • Senescence markers correlated with benign NF2 tumors, not malignant mesotheliomas.

Conclusions:

  • Yap is a central driver of proliferation in NF2 tumorigenesis.
  • Rac1 modulates inflammation and cell fate through reactive oxygen species production.
  • Senescence may contribute to the benign nature of most NF2-associated tumors.
Keywords:
DNA damage responseNF2ROSRac1Yapinflammationsenescence

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