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Science. 2018 Jul 27;361(6400):406-411. doi: 10.1126/science.aan3975.

LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis.

Author information

1
Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
2
Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
3
Department of Medicine, McGill University, Montreal, Quebec H3G 2M1, Canada.
4
Genentech, 1 DNA Way South, San Francisco, CA 94080, USA.
5
Faculty of Pharmacy, University of Montreal, Montreal, Quebec H3C 3J7, Canada.
6
Trev and Joyce Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia V8R 6V5, Canada.
7
Research Institute of the McGill University Health Centre, Montreal, Quebec H3H 2R9, Canada.
8
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
9
Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
10
Center for Human Immunology and Immunotherapy Programs, Washington University at St. Louis, St. Louis, MO 63110, USA.
11
Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 2Y2, Canada.
12
Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada. russell.jones@mcgill.ca russell.jones@vai.org.
13
Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.

Abstract

Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz-Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/- mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/- animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.

PMID:
30049881
DOI:
10.1126/science.aan3975
[Indexed for MEDLINE]

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