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LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis

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Science  27 Jul 2018:
Vol. 361, Issue 6400, pp. 406-411
DOI: 10.1126/science.aan3975

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Inflammation promotes gut polyposis

Peutz–Jeghers Syndrome (PJS) causes benign polyps in the gut and a higher risk of several cancers caused by mutations in the tumor suppressor gene STK11, which encodes liver kinase B1 (LKB1). LKB1's role in this disease is thought to be related to its tumor suppressor function. Now, Poffenberger et al. show that the T cell–specific heterozygous deletion of Stk11 is sufficient to reproduce PJS symptoms in mice (see the Perspective by Hollstein and Shaw). Polyps in mice and humans are characterized by immune cell infiltration, enhanced STAT3 signaling, and increased levels of inflammatory cytokines such as interleukin-6 (IL-6). Targeting STAT3 signaling, IL-6, or T cells ameliorated the polyps, suggesting potential therapies for this disease.

Science, this issue p. 406; see also p. 332

Abstract

Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz–Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/− mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/ animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.

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