Oncogenic kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia

Florencia McAllister, Jennifer M. Bailey, Janivette Alsina, Christopher J. Nirschl, Rajni Sharma, Hongni Fan, Yanique Rattigan, Jeffrey C. Roeser, Rachana H. Lankapalli, Hao Zhang, Elizabeth M. Jaffee, Charles G. Drake, Franck Housseau, Anirban Maitra, Jay K. Kolls, Cynthia L. Sears, Drew M. Pardoll, Steven D. Leach

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)621-637
Number of pages17
JournalCancer cell
Volume25
Issue number5
DOIs
StatePublished - May 12 2014

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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