title: GM-CSF Mediates Mesenchymal-Epithelial Cross-talk in Pancreatic Cancer.
abstract: Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense stroma consisting of a prevalence of activated fibroblasts whose functional contributions to pancreatic tumorigenesis remain incompletely understood. In this study, we provide the first identification and characterization of mesenchymal stem cells (MSC) within the human PDA microenvironment, highlighting the heterogeneity of the fibroblast population. Primary patient PDA samples and low-passage human pancreatic cancer-associated fibroblast cultures were found to contain a unique population of cancer-associated MSCs (CA-MSC). CA-MSCs markedly enhanced the growth, invasion, and metastatic potential of PDA cancer cells. CA-MSCs secreted the cytokine GM-CSF that was required for tumor cell proliferation, invasion, and transendothelial migration. Depletion of GM-CSF in CA-MSCs inhibited the ability of these cells to promote tumor cell growth and metastasis. Together, these data identify a population of MSCs within the tumor microenvironment that possesses a unique ability, through GM-CSF signaling, to promote PDA survival and metastasis.
  
  
  
  The role of stroma in pancreatic cancer is controversial. Here, we provide the first characterization of MSCs within the human PDA microenvironment and demonstrate that CA-MSCs promote tumorigenesis through the production of GM-CSF. These data identify a novel cytokine pathway that mediates mesenchymal-epithelial cross-talk and is amenable to therapeutic intervention. Cancer Discov; 6(8); 886-99. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Meghna
authors.initials: M
authors.lastname: Waghray
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Malica
authors.initials: M
authors.lastname: Yalamanchili
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Michele
authors.initials: M
authors.lastname: Dziubinski
authors.affiliation: Translational Oncology Program, University of Michigan, Ann Arbor, Michigan. Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
authors.forename: Mina
authors.initials: M
authors.lastname: Zeinali
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Marguerite
authors.initials: M
authors.lastname: Erkkinen
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Huibin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kara A
authors.initials: KA
authors.lastname: Schradle
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sumithra
authors.initials: S
authors.lastname: Urs
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca Di Magliano
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Theodore H
authors.initials: TH
authors.lastname: Welling
authors.affiliation: Translational Oncology Program, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Palmbos
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ethan V
authors.initials: EV
authors.lastname: Abel
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Sahai
authors.affiliation: Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan. Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Nagrath
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Lidong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan. Pancreatic Cancer Center, University of Michigan, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan, Ann Arbor, Michigan. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. simeone@med.umich.edu.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
mesh_terms: D000818:Animals; D015415:Biomarkers; D002450:Cell Communication; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D016130:Immunophenotyping; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: D015415:Biomarkers; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor