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

Saara Ollila 1, 2, 3 Eva Domènech-Moreno 1, 2 Kaisa Laajanen 1, 2 Iris Pl Wong 1, 2 Sushil Tripathi 1, 2 Nalle Pentinmikko 4 Yajing Gao 1, 2 Yan Yan 1, 2 Elina Niemelä 1, 2 Timothy Wang 3 Benoit Viollet 5, * Gustavo Leone 6 Pekka Katajisto 2, 4, 7 Kari Vaahtomeri 1 Tomi Mäkelä 1
* Corresponding author
1 Research Programs Unit [Helsinki, Finland]
2 HiLIFE - Helsinki Institute of Life Science [Helsinki, Finlande]
3 Department of Medicine - Division of Digestive and Liver Diseases [New York, NY, USA]
4 Institute of Biotechnology [Helsinki, Finlande]
5 EMD - [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD)
6 OSU - Ohio State University [Columbus]
7 Department of Biosciences and Nutrition [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
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Submitted on : Tuesday, November 5, 2019 - 8:00:07 PM
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Saara Ollila, Eva Domènech-Moreno, Kaisa Laajanen, Iris Pl Wong, Sushil Tripathi, et al.. Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway. Journal of Clinical Investigation, American Society for Clinical Investigation, 2018, 128 (1), pp.402-414. ⟨10.1172/JCI93597⟩. ⟨inserm-02349917⟩

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