title: Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia.
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-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.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Pitarresi
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sudarshana M
authors.initials: SM
authors.lastname: Sharma
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cuitiño
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Raleigh D
authors.initials: RD
authors.lastname: Kladney
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mace
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sydney
authors.initials: S
authors.lastname: Donohue
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sunayana G
authors.initials: SG
authors.lastname: Nayak
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Chunjing
authors.initials: C
authors.lastname: Qu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: James
authors.initials: J
authors.lastname: Lee
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Woelke
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Trela
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: LaPak
authors.affiliation: Department of Biomedical Informatics' Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Biomedical Informatics' Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: McElroy
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Shakya
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.affiliation: Department of Biomedical Informatics' Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Soledad A
authors.initials: SA
authors.lastname: Fernandez
authors.affiliation: Department of Biological Sciences and the Purdue Center for Cancer Research and the Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907-2057, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jinghai
authors.initials: J
authors.lastname: Wu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA. Electronic address: michael.ostrowski@osumc.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
mesh_terms: D061354:Acinar Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018925:Chemokines / Q000096:biosynthesis*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D010183:Pancreatic Ducts / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: D018925:Chemokines; D050787:Proto-Oncogene Protein c-ets-2; D003094:Collagen; D016283:Proto-Oncogene Proteins p21(ras)