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.

Si Ming Man ¹, Qifan Zhu ², Liqin Zhu ³, Zhiping Liu ⁴, Rajendra Karki ¹, Ankit Malik ¹, Deepika Sharma ¹, Liyuan Li ³, R K Subbarao Malireddi ¹, Prajwal Gurung ¹, Geoffrey Neale ⁵, Scott R Olsen ⁵, Robert A Carter ⁶, Daniel J McGoldrick ⁶, Gang Wu ⁶, David Finkelstein ⁶, Peter Vogel ⁷, Richard J Gilbertson ⁸, Thirumala-Devi Kanneganti ⁹

Affiliations

1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
3 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Biochemistry and Molecular Biology, School of Basic Medicines, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
5 Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7 Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
9 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: thirumala-devi.kanneganti@stjude.org.

PMID: 26095253 DOI: 10.1016/j.cell.2015.06.001

Abstract

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.

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