title: Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer.
abstract: Pancreatic cancer (PC) mobilizes myeloid cells from the bone marrow to the tumor where they promote tumor growth and proliferation. Cancer stem cells (CSCs) are a population of tumor cells that are responsible for tumor initiation. Aldehyde dehydrogenase-1 activity in PC identifies CSCs, and its activity has been correlated with poor overall prognosis in human PC. Myeloid cells have been shown to impact tumor stemness, but the impact of immunosuppressive tumor-infiltrating granulocytic and monocytic myeloid-derived suppressor cells (Mo-MDSC) on ALDH1(Bright) CSCs and epithelial to mesenchymal transition is not well understood. In this study, we demonstrate that Mo-MDSC (CD11b(+)/Gr1(+)/Ly6G(-)/Ly6C(hi)) significantly increase the frequency of ALDH1(Bright) CSCs in a mouse model of PC. Additionally, there was significant upregulation of genes associated with epithelial to mesenchymal transition. We also found that human PC converts CD14(+) peripheral blood monocytes into Mo-MDSC (CD14(+)/HLA-DR(low/-)) in vitro, and this transformation is dependent on the activation of the STAT3 pathway. In turn, these Mo-MDSC increase the frequency of ALDH1(Bright) CSCs and promote mesenchymal features of tumor cells. Finally, blockade of STAT3 activation reversed the increase in ALDH1(Bright) CSCs. These data suggest that the PC tumor microenvironment transforms monocytes to Mo-MDSC by STAT3 activation, and these cells increase the frequency of ALDH1(Bright) CSCs. Therefore, targeting STAT3 activation may be an effective therapeutic strategy in targeting CSCs in PC.
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Ave., Box 8109, St. Louis, MO, 63110, USA, pannir@wudosis.wustl.edu.
authors.forename: Roheena Z
authors.initials: RZ
authors.lastname: Panni
authors.forename: Dominic E
authors.initials: DE
authors.lastname: Sanford
authors.forename: Brian A
authors.initials: BA
authors.lastname: Belt
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Mitchem
authors.forename: Lori A
authors.initials: LA
authors.lastname: Worley
authors.forename: Brian D
authors.initials: BD
authors.lastname: Goetz
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: David G
authors.initials: DG
authors.lastname: Denardo
authors.forename: S Peter
authors.initials: SP
authors.lastname: Goedegebuure
authors.forename: David C
authors.initials: DC
authors.lastname: Linehan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human