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Genome-wide identification of genetic modifiers of Pak1-dependent skin tumor susceptibility in mice

Kazuhiro Okumura1, Megumi Saito1, Keisuke Otoyama1

  • 1Division of Experimental Animal Research, Cancer Genome Center, Chiba Cancer Center Research Institute.

Experimental Animals
|August 23, 2026
PubMed

Insights

Researchers identified genetic modifiers affecting skin tumor susceptibility in mice with reduced Pak1 in immune cells. Key loci, Pm1 and Pm3, interact to influence tumor development, revealing a genetic framework for immune-mediated carcinogenesis.

Area of Science:

  • Immunology
  • Genetics
  • Oncology

Background:

  • Pak1 (p21-activated kinase 1) is a kinase involved in tumor progression and immune responses.
  • Genetic modifiers of resistance due to Pak1 deficiency in CD11c-positive immune cells are not well understood.

Purpose of the Study:

  • To identify genetic modifiers influencing tumor susceptibility in mice with Pak1-deficient immune cells.
  • To elucidate the genetic framework underlying immune-mediated skin carcinogenesis.

Main Methods:

  • A forward genetic screen was performed using Cd11cCre-Pak1fl/+ F1 backcross mice.
  • Genome-wide genotyping with GRAS-Di identified 14,053 markers.
  • Principal component-adjusted generalized linear models (GLMs) were used for analysis.

Main Results:

  • Nine genome-wide significant Pak1 modifier loci (Pm1-Pm9) associated with tumor susceptibility were identified.
  • Pm1 on chromosome 5 showed the strongest association with papilloma and carcinoma.
  • Epistasis analysis revealed Pm3 on chromosome 4 attenuates Pm1's tumor-promoting effect.

Conclusions:

  • A genetic framework involving the Pm1/Pm3 axis in Pak1-reduced skin carcinogenesis was delineated.
  • Immune regulators modulate tumor susceptibility in a Pak1-reduced immune compartment.
  • Findings highlight the interplay between immune cells and genetic factors in cancer development.
Keywords:
Cd11cCreDMBA/TPAPak1genome-wide association study (GWAS)

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