Journal
CELL REPORTS
Volume 19, Issue 7, Pages 1322-1333Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.04.052
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Funding
- Chartrand Foundation
- Hirshberg Foundation for Pancreatic Cancer Research, American Cancer Society [RSG-12-083-01-TBG]
- Mayo Clinic SPORE in Pancreatic Cancer [CA102701-12DRP3]
- [NIH CA200572]
- [NIH P01 CA117969-07]
- [NIH P01 CA163200]
- [P01 DK098108]
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The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM]), which then gives rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly decreased the accumulation of alternatively activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.
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