title: Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer.
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.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Si Ming
authors.initials: SM
authors.lastname: Man
authors.affiliation: 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.
authors.forename: Qifan
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Liqin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Karki
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Malik
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Deepika
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: R K Subbarao
authors.initials: RK
authors.lastname: Malireddi
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Gurung
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Olsen
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Carter
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McGoldrick
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: 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.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: thirumala-devi.kanneganti@stjude.org.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D000818:Animals; D001397:Azoxymethane; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016264:Dextran Sulfate; D020895:Enterocytes / Q000473:pathology; D041981:Gastrointestinal Tract / Q000382:microbiology; D058847:Inflammasomes / Q000378:metabolism; D051379:Mice; D009154:Mutation; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D016264:Dextran Sulfate; D001397:Azoxymethane