Journal
CANCER RESEARCH
Volume 79, Issue 20, Pages 5316-5327Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-3064
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Funding
- NIH/NIDDK [DK101413]
- National Pancreas Foundation
- Children's Hospital of Pittsburgh of UPMC
- Cancer Research UK [C29717/A17263, C29717/A18484, C596/A18076, C596/A20921, A23526]
- Wellcome Trust [103721/Z/14/Z]
- Pancreatic Cancer UK Future Research Leaders Fund [FLF2015_04_Glasgow]
- Scottish Genome Partnership [SEHHD-CSO 1175759/2158447]
- MRC/EPSRC Glasgow Molecular Pathology Node
- Howat Foundation
- Cancer Center Support Grant, National Cancer Institute, Bethesda, Maryland [P30 CA016058]
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Pancreatic ductal adenocarcinoma (PDAC) is associated with significant fibrosis. Recent findings have highlighted the profibrotic activity of tissue-resident macrophages in the pancreatic cancer microenvironment. Here, we show that neoplastic pancreatic epithelium, as well as a subset of tissue-resident macrophages, expresses the prolactin-receptor (PRLR). High mobility group box 1-induced prolactin expression in the pancreas maintained FAK1 and STAT3 phosphorylation within the epithelium and stroma. Gain-of-function and loss-of-function experiments demonstrated the essential role of prolactin in promoting collagen deposition and fibrosis. Finally, the signaling cascade downstream of prolactin/PRLR activated STAT3 rather than STAT5 in PDAC. These findings suggest that targeting prolactin together with IL6, a known major activator of STAT3, could represent a novel therapeutic strategy for treating pancreatic cancer. Significance: Prolactin is a key factor in the cross-talk between the stroma and neoplastic epithelium, functioning to promote fibrosis and PDAC progression.
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