Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia.
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 Kras(G12D) 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 in vivo 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.
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA; Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Florencia
F
McAllister
Department of Surgery and McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Jennifer M
JM
Bailey
Department of Surgery and McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Janivette
J
Alsina
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
Christopher J
CJ
Nirschl
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21205, USA.
Rajni
R
Sharma
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
Hongni
H
Fan
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21205, USA.
Yanique
Y
Rattigan
Department of Surgery and McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Jeffrey C
JC
Roeser
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
Rachana H
RH
Lankapalli
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Hao
H
Zhang
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
Elizabeth M
EM
Jaffee
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
Charles G
CG
Drake
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
Franck
F
Housseau
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21205, USA.
Anirban
A
Maitra
Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
Jay K
JK
Kolls
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
Cynthia L
CL
Sears
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
Drew M
DM
Pardoll
Department of Surgery and McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: leachs@mskcc.org.
Steven D
SD
Leach
D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D002471:Cell Transformation, Neoplastic; D018890:Chemoprevention; D004847:Epithelial Cells / Q000378:metabolism*; D006413:Hematopoietic System / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology
C098680:Il17a protein, mouse; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D053722:Receptors, Interleukin-17; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)