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Journal articles
Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway
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.
Cited literature [74 references]
https://www.hal.inserm.fr/inserm-02349917
Contributor : Benoit Viollet <>
Submitted on : Tuesday, November 5, 2019 - 8:00:07 PM
Last modification on : Thursday, April 9, 2020 - 11:59:28 AM
Long-term archiving on: : Friday, February 7, 2020 - 5:23:53 AM
Contributor : Benoit Viollet <>
Submitted on : Tuesday, November 5, 2019 - 8:00:07 PM
Last modification on : Thursday, April 9, 2020 - 11:59:28 AM
Long-term archiving on: : Friday, February 7, 2020 - 5:23:53 AM