Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer

Cell. 2015 Jul 2;162(1):45-58. doi: 10.1016/j.cell.2015.06.001. Epub 2015 Jun 18.


Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azoxymethane
  • Cell Proliferation*
  • Colitis / chemically induced
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • DNA-Binding Proteins / metabolism*
  • Dextran Sulfate
  • Enterocytes / pathology
  • Gastrointestinal Tract / microbiology
  • Inflammasomes / metabolism
  • Mice
  • Mutation
  • Stem Cells / metabolism
  • Stem Cells / pathology*


  • Aim2 protein, mouse
  • DNA-Binding Proteins
  • Inflammasomes
  • Dextran Sulfate
  • Azoxymethane

Associated data

  • GEO/GSE69436
  • SRA/SRP059020