TY - JOUR
T1 - LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis
AU - Poffenberger, M. C.
AU - Metcalfe-Roach, A.
AU - Aguilar, E.
AU - Chen, J.
AU - Hsu, B. E.
AU - Wong, A. H.
AU - Johnson, R. M.
AU - Flynn, B.
AU - Samborska, B.
AU - Ma, E. H.
AU - Gravel, S. P.
AU - Tonelli, L.
AU - Devorkin, L.
AU - Kim, P.
AU - Hall, A.
AU - Izreig, S.
AU - Loginicheva, E.
AU - Beauchemin, N.
AU - Siegel, P. M.
AU - Artyomov, M. N.
AU - Lum, J. J.
AU - Zogopoulos, G.
AU - Blagih, J.
AU - Jones, R. G.
N1 - Publisher Copyright:
© 2018 Academic Press. All rights reserved.
PY - 2018/7/27
Y1 - 2018/7/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85050899317&partnerID=8YFLogxK
U2 - 10.1126/science.aan3975
DO - 10.1126/science.aan3975
M3 - Article
C2 - 30049881
AN - SCOPUS:85050899317
SN - 0036-8075
VL - 361
SP - 406
EP - 411
JO - Science
JF - Science
IS - 6400
ER -