TY - JOUR
T1 - Oncogenic kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia
AU - McAllister, Florencia
AU - Bailey, Jennifer M.
AU - Alsina, Janivette
AU - Nirschl, Christopher J.
AU - Sharma, Rajni
AU - Fan, Hongni
AU - Rattigan, Yanique
AU - Roeser, Jeffrey C.
AU - Lankapalli, Rachana H.
AU - Zhang, Hao
AU - Jaffee, Elizabeth M.
AU - Drake, Charles G.
AU - Housseau, Franck
AU - Maitra, Anirban
AU - Kolls, Jay K.
AU - Sears, Cynthia L.
AU - Pardoll, Drew M.
AU - Leach, Steven D.
N1 - Funding Information:
The authors wish to thank Danielle Blake, Mara Swaim, Anzer Habibulla, and Xinqun Wu for expert technical assistance, Mary Armanios for helpful discussions, Amgen for the generous provision of neutralizing antibodies, Haiping Hao and Connie Talbot for microarray and bioinformatics support, and Prof. Yoichiro Iwakura (The University of Tokyo, Tokyo, Japan) for kindly providing the IL-17A knockout mice. F.M. was supported by National Institute of General Medical Sciences (NIGMS) T32GMO66691, 2012 Pancreatic Cancer Action Network-AACR Fellowship, in memory of Samuel Stroum, grant 12-40-25-MCAL, and Conquer Cancer Foundation Young Investigator Award 2012. S.D.L. and A.M. were supported by National Cancer Institute (NCI) P01 CA134292. S.D.L. was further supported by the Paul K. Neumann Professorship in Pancreatic Cancer at Johns Hopkins University. J.M.B. was supported by the PanCAN-AACR Pathway to Leadership Award and NCI F32 CA157044. J.A. was supported by NCI T32CA126607 fellowship and an ImmixGroup Foundation Fellowship.
PY - 2014/5/12
Y1 - 2014/5/12
N2 - Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that KrasG12D induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional invivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.
AB - Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that KrasG12D induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional invivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.
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U2 - 10.1016/j.ccr.2014.03.014
DO - 10.1016/j.ccr.2014.03.014
M3 - Article
C2 - 24823639
AN - SCOPUS:84900315697
SN - 1535-6108
VL - 25
SP - 621
EP - 637
JO - Cancer cell
JF - Cancer cell
IS - 5
ER -