stromal ets2 regulates chemokine production and immune cell recruitment during acinar-to-ductal metaplasia

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ID: 245476
2016
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Abstract
Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin–positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls. LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice showed that ETS2 expression initially increased in fibroblasts during ADM and remained elevated through progression to PDAC. Conditional ablation of Ets-2 in pancreatic fibroblasts in a KrasG12D-driven mouse ADM model decreased the amount of ADM events. ADMs from fibroblast Ets-2–deleted animals had reduced epithelial cell proliferation and increased apoptosis. Surprisingly, fibroblast Ets-2 deletion significantly altered immune cell infiltration into the stroma, with an increased CD8+ T-cell population, and decreased presence of regulatory T cells (Tregs), myeloid-derived suppressor cells, and mature macrophages. The mechanism involved ETS2-dependent chemokine ligand production in fibroblasts. ETS2 directly bound to regulatory sequences for Ccl3, Ccl4, Cxcl4, Cxcl5, and Cxcl10, a group of chemokines that act as potent mediators of immune cell recruitment. These results suggest an unappreciated role for ETS2 in fibroblasts in establishing an immune-suppressive microenvironment in response to oncogenic KrasG12D signaling during the initial stages of tumor development.
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pitarresi2016neoplasia:stromal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Jason R. Pitarresi;Xin Liu;Sudarshana M. Sharma;Maria C. Cuitiño;Raleigh D. Kladney;Thomas A. Mace;Sydney Donohue;Sunayana G. Nayak;Chunjing Qu;James Lee;Sarah A. Woelke;Stefan Trela;Kyle LaPak;Lianbo Yu;Joseph McElroy;Thomas J. Rosol;Reena Shakya;Thomas Ludwig;Gregory B. Lesinski;Soledad A. Fernandez;Stephen F. Konieczny;Gustavo Leone;Jinghai Wu;Michael C. Ostrowski
Journal ACS chemical neuroscience
Year 2016
DOI
10.1016/j.neo.2016.07.006
URL
http://www.sciencedirect.com/science/article/pii/S1476558616300367
Keywords
neoplasms Oncology including cancer and carcinogens tumors

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