RT Journal Article
SR Electronic
T1 GM-CSF Mediates Mesenchymal–Epithelial Cross-talk in Pancreatic Cancer
JF Cancer Discovery
JO Cancer Discov
FD American Association for Cancer Research
SP 886
OP 899
DO 10.1158/2159-8290.CD-15-0947
VO 6
IS 8
A1 Waghray, Meghna
A1 Yalamanchili, Malica
A1 Dziubinski, Michele
A1 Zeinali, Mina
A1 Erkkinen, Marguerite
A1 Yang, Huibin
A1 Schradle, Kara A.
A1 Urs, Sumithra
A1 Pasca Di Magliano, Marina
A1 Welling, Theodore H.
A1 Palmbos, Phillip L.
A1 Abel, Ethan V.
A1 Sahai, Vaibhav
A1 Nagrath, Sunitha
A1 Wang, Lidong
A1 Simeone, Diane M.
YR 2016
UL http://cancerdiscovery.aacrjournals.org/content/6/8/886.abstract
AB 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.Significance: 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