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 - Funding Information:
This work was supported by grants from the Canadian Cancer Society (CCSRI; 702566 to R.G.J.) and the Canadian Institutes of Health Research (CIHR; MOP-93799 and PJT-156397 to R.G.J., MOP-86582 to N.B., and MOP-142351 to J.J.L.). Fellowship support was provided from the McGill Integrated Cancer Research Training Program (to B.F., J.C., and E.H.M.), the Defi Canderel (to M.C.P.), the Fonds de Recherche du Québec-Santé (FRQS; to M.C.P., E.H.M., G.Z., and J.B.), and the CIHR (to M.C.P. and R.G.J.)
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 -