Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia

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• 作者：Jason R. Pitarresi^* ; ^&dagger ; ; Xin Liu^* ; ^&dagger ; ; Sudarshana M. Sharma^* ; ^&dagger ; ; Maria C. Cuitiñ ; o^* ; ^&dagger ; ; Raleigh D. Kladney^* ; ^&dagger ; ; Thomas A. Mace^* ; ^&Dagger ; ; Sydney Donohue^* ; ^&dagger ; ; Sunayana G. Nayak^* ; ^&dagger ; ; Chunjing Qu^# ; James Lee^* ; ^&dagger ; ; Sarah A. Woelke^* ; ^&dagger ; ; Stefan Trela^* ; ^&dagger ; ; Kyle LaPak^* ; ^&dagger ; ; Lianbo Yu^§ ; ; Joseph McElroy^§ ; ; Thomas J. Rosol^* ; ^¶ ; ; Reena Shakya^* ; ^&dagger ; ; Thomas Ludwig^* ; ^&dagger ; ; Gregory B. Lesinski^* ; ^&Dagger ; ; Soledad A. Fernandez^§ ; ; Stephen F. Konieczny^# ; Gustavo Leone^* ; ^&dagger ; ; Jinghai Wu^* ; ^&dagger ; ; Michael C. Ostrowski^* ; ^&dagger ; ; ^{michael.ostrowski@osumc.edu" class="auth_mail" title="E-mail the corresponding author}
• 刊名：Neoplasia
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：18
• 期：9
• 页码：541-552
• 全文大小：3431 K

文摘

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-Kras^G12D/+; LSL-Trp53^R172H/+; 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 Kras^G12D-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 Kras^G12D signaling during the initial stages of tumor development.