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Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway
Saara Ollila, … , Kari Vaahtomeri, Tomi P. Mäkelä
Saara Ollila, … , Kari Vaahtomeri, Tomi P. Mäkelä
Published December 4, 2017
Citation Information: J Clin Invest. 2018;128(1):402-414. https://doi.org/10.1172/JCI93597.
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Research Article Gastroenterology Oncology

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

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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.

Authors

Saara Ollila, Eva Domènech-Moreno, Kaisa Laajanen, Iris P.L. Wong, Sushil Tripathi, Nalle Pentinmikko, Yajing Gao, Yan Yan, Elina H. Niemelä, Timothy C. Wang, Benoit Viollet, Gustavo Leone, Pekka Katajisto, Kari Vaahtomeri, Tomi P. Mäkelä

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Figure 4

Inactivation of AMPK does not lead to polyposis.

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Inactivation of AMPK does not lead to polyposis.
(A) Representative imag...
(A) Representative images of stomachs at 8 months of age with genotypes indicated. (B) Polyp number (left) and diameter (right) of mice of indicated genotypes at 8 months of age. Lkb1+/+;AMPKa1–/– (n = 4), Lkb1+/–; AMPKa1+/+ (n = 9), Lkb1+/-; AMPKa1–/– (n = 8). Lines depict mean and standard deviation. (C) Average polyp number (left) and diameter (right) of mice of indicated genotypes at 8 months of age. Lkb1+/+; AMPKa2–/– (n = 6), Lkb1+/–; AMPKa2+/+ (n = 10), Lkb1+/–; AMPKa2–/– (n = 10). Lines depict mean and standard deviation. (D) Representative images of stomachs at 17 months of age with genotypes indicated. (E) Average polyp number (left) and diameter (right) of mice of indicated genotypes at 17 months of age. Lkb1FspKO/+ (n = 27), AMPKa1–/–; AMPKa2FspKO/FspKO (n = 12). *P < 0.05 as assessed by unpaired t test. n.s., not significant. Lines in graphs depict mean and standard deviation. Two-tailed unpaired t test was used as a statistical test. Scale bars: 5 mm. nr, number; n.s., not significant.

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