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

doi:10.1016/j.cell.2015.06.001

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

Journal article

Open access

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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, …

Cell, Vol.162(1), pp.45-58

07/02/2015

DOI: 10.1016/j.cell.2015.06.001

PMCID: PMC4491002

PMID: 26095253

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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.

Mutation

Dextran Sulfate

Cell Proliferation

Inflammasomes - metabolism

Colorectal Neoplasms - genetics

Gastrointestinal Tract - microbiology

Stem Cells - metabolism

DNA-Binding Proteins - metabolism

Animals

Azoxymethane

Colorectal Neoplasms - immunology

Colitis - chemically induced

Stem Cells - pathology

Enterocytes - pathology

Mice

Colorectal Neoplasms - pathology

Colorectal Neoplasms - metabolism

Details

Title: Subtitle: Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer
Creators: Si Ming Man - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Qifan Zhu - 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
Liqin Zhu - Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Zhiping Liu - 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
Rajendra Karki - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Ankit Malik - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Deepika Sharma - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Liyuan Li - Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
R K Subbarao Malireddi - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Prajwal Gurung - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Geoffrey Neale - Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Scott R Olsen - Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Robert A Carter - Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Daniel J McGoldrick - Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Gang Wu - Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
David Finkelstein - Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Peter Vogel - Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Richard J Gilbertson - 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
Thirumala-Devi Kanneganti - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: thirumala-devi.kanneganti@stjude.org
Resource Type: Journal article
Publication Details: Cell, Vol.162(1), pp.45-58
DOI: 10.1016/j.cell.2015.06.001
PMID: 26095253
PMCID: PMC4491002
ISSN: 0092-8674
eISSN: 1097-4172
Grant note: R01 AI101935 / NIAID NIH HHS R01 CA163507 / NCI NIH HHS P30 CA021765 / NCI NIH HHS R01 AR056296 / NIAMS NIH HHS AI101935 / NIAID NIH HHS CA163507 / NCI NIH HHS P01 CA096832 / NCI NIH HHS AR056296 / NIAMS NIH HHS
Language: English
Date published: 07/02/2015
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094504302771

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