Format

Send to

Choose Destination
J Clin Invest. 2018 Jan 2;128(1):402-414. doi: 10.1172/JCI93597. Epub 2017 Dec 4.

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11-JAK/STAT3 pathway.

Author information

1
Research Programs Unit, Faculty of Medicine and.
2
HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
3
Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University Medical Center, New York, New York, USA.
4
Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
5
INSERM, U1016, Institut Cochin, Paris, France.
6
CNRS, UMR8104, Paris, France.
7
Université Paris Descartes, Sorbonne Paris Cité, France.
8
Department of Cancer Biology and Genetics, College of Medicine, Department of Molecular Genetics, College of Biological Sciences, and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
9
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

Abstract

Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast-specific deletion of Lkb1 results in fully penetrant polyposis in mice. Lineage tracing and immunohistochemical analyses revealed clonal expansion of Lkb1-deficient myofibroblast-like cell foci in the tumor stroma. Loss of Lkb1 in stromal cells was associated with induction of an inflammatory program including IL-11 production and activation of the JAK/STAT3 pathway in tumor epithelia concomitant with proliferation. Importantly, treatment of LKB1-defcient mice with the JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis. These data indicate that IL-11-mediated induction of JAK/STAT3 is critical in gastrointestinal tumorigenesis following Lkb1 mutations and suggest that targeting this pathway has therapeutic potential in Peutz-Jeghers syndrome.

KEYWORDS:

Gastric cancer; Gastroenterology; Mouse models; Oncology; Tumor suppressors

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center