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Updated: Feb 5, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11-JAK/STAT3 pathway
Saara Ollila1,2,3, Eva Domènech-Moreno1,2, Kaisa Laajanen1,2
1Research Programs Unit, Faculty of Medicine and.
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.
Insights
Loss of the LKB1 tumor suppressor in stromal cells drives gastrointestinal polyps by activating IL-11 and JAK/STAT3 signaling. Targeting this pathway with ruxolitinib reduced tumor growth in Peutz-Jeghers syndrome models.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- Peutz-Jeghers syndrome (PJS) is linked to germline mutations in the LKB1 gene, a tumor suppressor kinase.
- The specific cell types and molecular pathways driving PJS-associated gastrointestinal tumorigenesis remain largely undetermined.
Purpose of the Study:
- To elucidate the cellular origin and signaling mechanisms of LKB1-deficient gastrointestinal tumor formation.
- To investigate the therapeutic potential of targeting identified pathways in PJS.
Main Methods:
- Mice with conditional Lkb1 deletion in mesenchymal progenitor or stromal fibroblast populations were utilized.
- Lineage tracing, immunohistochemistry, and JAK/STAT3 pathway inhibition (ruxolitinib) were employed.
Main Results:
- Lkb1 deletion in stromal cells led to fully penetrant polyposis in mice.
- Lkb1-deficient stromal cells formed myofibroblast-like foci, inducing an inflammatory program with IL-11 production.
- IL-11 activated JAK/STAT3 signaling in tumor epithelia, promoting proliferation.
- Ruxolitinib treatment significantly reduced polyposis in Lkb1-deficient mice.
Conclusions:
- Stromal LKB1 loss initiates PJS tumorigenesis via IL-11 and JAK/STAT3 pathway activation.
- The IL-11/JAK/STAT3 axis is a critical driver of gastrointestinal tumor development in LKB1-mutant PJS.
- Targeting the JAK/STAT3 pathway represents a promising therapeutic strategy for Peutz-Jeghers syndrome.
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