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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.

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Research Programs Unit, Faculty of Medicine and.
HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University Medical Center, New York, New York, USA.
Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
INSERM, U1016, Institut Cochin, Paris, France.
CNRS, UMR8104, Paris, France.
Université Paris Descartes, Sorbonne Paris Cité, France.
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.
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.


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.


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

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