LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis.
Poffenberger M C,Metcalfe-Roach A,Aguilar E,Chen J,Hsu B E,Wong A H,Johnson R M,Flynn B,Samborska B,Ma E H,Gravel S-P,Tonelli L,Devorkin L,Kim P,Hall A,Izreig S,Loginicheva E,Beauchemin N,Siegel P M,Artyomov M N,Lum J J,Zogopoulos G,Blagih J,Jones R G
Science (New York, N.Y.)
Germline mutations in , 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 in T cells (LT mice) is sufficient to promote GI polyposis. Polyps from LT mice, 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 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.