title: Interleukin-6/STAT3 Pathway Signaling Drives an Inflammatory Phenotype in Group A Ependymoma.
abstract: Ependymoma (EPN) in childhood is a brain tumor with substantial mortality. Inflammatory response has been identified as a molecular signature of high-risk Group A EPN. To better understand the biology of this phenotype and aid therapeutic development, transcriptomic data from Group A and B EPN patient tumor samples, and additional malignant and normal brain data, were analyzed to identify the mechanism underlying EPN Group A inflammation. Enrichment of IL6 and STAT3 pathway genes were found to distinguish Group A EPN from Group B EPN and other brain tumors, implicating an IL6 activation of STAT3 mechanism. EPN tumor cell growth was shown to be dependent on STAT3 activity, as demonstrated using shRNA knockdown and pharmacologic inhibition of STAT3 that blocked proliferation and induced apoptosis. The inflammatory factors secreted by EPN tumor cells were shown to reprogram myeloid cells, and this paracrine effect was characterized by a significant increase in pSTAT3 and IL8 secretion. Myeloid polarization was shown to be dependent on tumor secretion of IL6, and these effects could be reversed using IL6-neutralizing antibody or IL6 receptor-targeted therapeutic antibody tocilizumab. Polarized myeloid cell production of IL8 drove unpolarized myeloid cells to upregulate CD163 and to produce a number of proinflammatory cytokines. Collectively, these findings indicate that constitutive IL6/STAT3 pathway activation is important in driving tumor growth and inflammatory cross-talk with myeloid cells within the Group A EPN microenvironment. Effective design of Group A-targeted therapy for children with EPN may require reversal of this potentially immunosuppressive and protumor pathway.
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado. Children's Hospital Colorado, Aurora, Colorado. andrea.griesinger@ucdenver.edu.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Griesinger
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Josephson
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado. Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado. Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Mulcahy Levy
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado. Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Amani
authors.affiliation: Children's Hospital Colorado, Aurora, Colorado. Department of Neurosurgery, University of Colorado Denver, Aurora, Colorado.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.affiliation: Department of Cancer and Blood Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Hoffman
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Steffanie L
authors.initials: SL
authors.lastname: Furtek
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Phillip
authors.initials: P
authors.lastname: Reigan
authors.affiliation: Children's Hospital Colorado, Aurora, Colorado. Department of Neurosurgery, University of Colorado Denver, Aurora, Colorado.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Handler
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado. Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado. Children's Hospital Colorado, Aurora, Colorado. Department of Neurosurgery, University of Colorado Denver, Aurora, Colorado.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D004806:Ependymoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D050796:STAT3 Transcription Factor