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LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis

Nature Genetics volume 40, pages 455–459 (2008)Cite this article

Abstract

Germline mutations in STK11 (also known as LKB1) are found in individuals with Peutz-Jeghers syndrome (PJS)1 manifesting with gastrointestinal polyps that contain a prominent stromal component. Epithelia in polyps of Stk11+/− mice can retain a functional copy of Stk11 (refs. 2,3), and loss of heterozygosity is not an obligate feature of human polyps4, raising the possibility of non-epithelial origins in tumorigenesis. Here we show that either monoallelic or biallelic loss of murine Stk11 limited to Tagln-expressing mesenchymal cells results in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in PJS. Stk11-deficient mesenchymal cells produced less TGFβ, and defective TGFβ signaling to epithelial cells coincided with epithelial proliferation. We also noted TGFβ signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in PJS.

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Figure 1: Smooth-muscle targeted inactivation of Stk11 recapitulates polyp development in Stk11+/− mice.
Figure 2: Increased myofibroblast-like (SMA+ desmin−) cells in stromal areas with Stk11 recombination.
Figure 3: Decreased TGFβ signaling and associated epithelial proliferation following stromal Stk11 deletion.
Figure 4: Human Peutz-Jeghers syndrome polyps show increased SMA-positive myogenic cells in stroma and associated decrease of TGFβ signaling.

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Acknowledgements

We thank D. Rifkin (New York University Medical Center) and K. Koli (Haartman Institute, University of Helsinki) for reagents and advice on the TGFβ assays, and S. Räsänen, O. Kokkonen, J. Bärlund, B. Tjäder, S. Laine and K. Mänttäri for technical assistance. This work was supported by grants from the Academy of Finland, Biocentrum Helsinki, Finnish Cancer Organization, Ida Montin Foundation, Orion-Farmos Research Foundation and Sigrid Juselius Foundation. R.A.D. is an American Cancer Society Research Professor and is supported by grants from the US National Institutes of Health and the Belfer Foundation.

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Authors and Affiliations

  1. Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, 00014 University of Helsinki, Finland

    Pekka Katajisto, Kari Vaahtomeri, Niklas Ekman, Eeva Ventelä, Ari Ristimäki & Tomi P Mäkelä

  2. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland

    Ari Ristimäki

  3. Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Nabeel Bardeesy

  4. Interfakultäres Institut für Biochemie, Signaltransduktion-Transgene Modelle, Universität Tübingen, Hoppe-Seyler-Str. 4, Tübingen, 72076, Germany

    Robert Feil

  5. Departments of Medical Oncology, Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science, Medicine and Genetics, Dana Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Ronald A DePinho

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  1. Pekka Katajisto
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Correspondence to Tomi P Mäkelä.

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Katajisto, P., Vaahtomeri, K., Ekman, N. et al. LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Nat Genet 40, 455–459 (2008). https://doi.org/10.1038/ng.98

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