Ets-2 in Pancreatic Cancer Associated Fibroblasts Promotes Tumor Initiation and Development.
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Date
2014-02
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Abstract
Pancreatic cancer remains an overwhelmingly fatal disease with less than 5% of patients surviving beyond 5 years, largely due to our lack of understanding of the complexity of the disease. Many recent reports have begun to highlight the potential role that stromal cells—fibroblasts in particular—may have on pancreatic tumor cell biology and this report provides data that supports the theory of tumor-stroma co-evolution in pancreatic cancer. Here we use a novel mouse model to show that Ets-2 in the tumor-associated stroma promotes pancreatic tumor initiation and development. We observed a decrease in tumorigenesis events such as acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions when Ets-2 is conditionally deleted in pancreatic cancer associated fibroblasts (CAFs). To determine how Ets-2 in fibroblasts is able to effect tumor progression, we harvested pancreatic CAFs from Ets-2 deleted and Ets-2 intact tumor bearing mice and performed microarray gene expression analysis. We found that Ets-2 deleted CAFs had a significantly altered secretome that crucially lacked tumor necrosis factor alpha (TNF-α), a known pro-tumor ligand in pancreatic carcinogenesis. Furthermore, ChIP analysis showed that Ets-2 binds the proximal promoter of TNF-α to directly regulate its expression. Thus, Ets-2 ablation in pancreatic fibroblasts delays pancreatic tumor initiation by decreasing the pro-tumor ligand TNF-α. This report shows for the first time that deleting a gene in pancreatic fibroblasts causes a change in tumor-stroma co-evolution and that Ets-2 is able to act as a novel oncogene in cancer associated fibroblasts to promote pancreatic carcinogenesis.
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Poster Division: Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Pancreatic Cancer Associated Fibroblast