title: Cancer-associated adipose tissue promotes breast cancer progression by paracrine oncostatin M and Jak/STAT3 signaling.
abstract: Increasing evidence supports the critical roles played by adipose tissue in breast cancer progression. Yet, the mediators and mechanisms are poorly understood. Here, we show that breast cancer-associated adipose tissue from freshly isolated tumors promotes F-actin remodeling, cellular scattering, invasiveness, and spheroid reorganization of cultured breast cancer cells. A combination of techniques, including transcriptomics, proteomics, and kinomics enabled us to identify paracrine secretion of oncostatin M (OSM) by cancer-associated adipose tissue. Specifically, OSM, expressed by CD45(+) leucocytes in the stromal vascular fraction, induced phosphorylation of STAT3 (pSTAT3-) Y705 and S727 in breast cancer cells and transcription of several STAT3-dependent genes, including S100 family members S100A7, S100A8, and S100A9. Autocrine activation of STAT3 in MCF-7 cells ectopically expressing OSM-induced cellular scattering and peritumoral neovascularization of orthotopic xenografts. Conversely, selective inhibition of OSM by neutralizing antibody and Jak family kinases by tofacitinib inhibited STAT3 signaling, peritumoral angiogenesis, and cellular scattering. Importantly, nuclear staining of pSTAT3-Y705 identified at the tumor invasion front in ductal breast carcinomas correlates with increased lymphovascular invasion. Our work reveals the potential of novel therapeutic strategies targeting the OSM and STAT3 axis in patients with breast cancer harboring nuclear pSTAT3-Y705.
authors.affiliation: Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Lore
authors.initials: L
authors.lastname: Lapeire
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Hendrix
authors.affiliation: Department of Pathology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Lambein
authors.affiliation: Department of Pathology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Van Bockstal
authors.affiliation: Department of Gynaecology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Braems
authors.affiliation: Department of Gynaecology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Rudy
authors.initials: R
authors.lastname: Van Den Broecke
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.
authors.forename: Ridha
authors.initials: R
authors.lastname: Limame
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.affiliation: Institute Biomedical Technology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Vanhove
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
authors.forename: Dawn
authors.initials: D
authors.lastname: Maynard
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, UPS, Toulouse, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Lehuédé
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, UPS, Toulouse, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Muller
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM U1048, Université Paul Sabatier, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM U938, Molecular and Clinical Oncology, Université Paris VI Pierre et Marie Curie, Paris, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Gespach
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Bracke
authors.affiliation: Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Veronique
authors.initials: V
authors.lastname: Cocquyt
authors.affiliation: Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Denys
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium. olivier.dewever@ugent.be.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
mesh_terms: D000199:Actins / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D064593:Heterografts; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D053683:Oncostatin M / Q000378:metabolism*; D019899:Paracrine Communication; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000199:Actins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053683:Oncostatin M; D053612:Janus Kinases