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

Si Ming Man, Qifan Zhu, Liqin Zhu, Zhiping Liu, Rajendra Karki, Ankit Malik, Deepika Sharma, Liyuan Li, R. K.Subbarao Malireddi, Prajwal Gurung, Geoffrey Neale, Scott R. Olsen, Robert A. Carter, Daniel J. McGoldrick, Gang Wu, David Finkelstein, Peter Vogel, Richard J. Gilbertson, Thirumala Devi Kanneganti*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

262 Citations (Scopus)

Abstract

Summary 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.

Original languageEnglish
Pages (from-to)45-58
Number of pages14
JournalCell
Volume162
Issue number1
DOIs
Publication statusPublished - 3 Jul 2015
Externally publishedYes

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