title: Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation.
abstract: The tumour vascular microenvironment supports tumorigenesis not only by supplying oxygen and diffusible nutrients but also by secreting soluble factors that promote tumorigenesis. Here we identify a feedforward mechanism in which endothelial cells (ECs), in response to tumour-derived mediators, release angiocrines driving aberrant vascularization and glioblastoma multiforme (GBM) progression through a hypoxia-independent induction of hypoxia-inducible factor (HIF)-1α. Phosphorylation of profilin-1 (Pfn-1) at Tyr 129 in ECs induces binding to the tumour suppressor protein von Hippel-Lindau (VHL), and prevents VHL-mediated degradation of prolyl-hydroxylated HIF-1α, culminating in HIF-1α accumulation even in normoxia. Elevated HIF-1α induces expression of multiple angiogenic factors, leading to vascular abnormality and tumour progression. In a genetic model of GBM, mice with an EC-specific defect in Pfn-1 phosphorylation exhibit reduced tumour angiogenesis, normalized vasculature and improved survival. Moreover, EC-specific Pfn-1 phosphorylation is associated with tumour aggressiveness in human glioma. These findings suggest that targeting Pfn-1 phosphorylation may offer a selective strategy for therapeutic intervention of malignant solid tumours.
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA [2] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA [2] Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue Cleveland, Ohio 44106, USA.
authors.forename: Alka A
authors.initials: AA
authors.lastname: Potdar
authors.affiliation: 1] Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA [2] Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA.
authors.forename: Sandeepa M
authors.initials: SM
authors.lastname: Eswarappa
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Donnola
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: 1] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA [2] Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Hambardzumyan
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue Cleveland, Ohio 44195, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D051304:Profilins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment; D014443:Tyrosine; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495738:PFN1 protein, human; C495739:Pfn1 protein, mouse; D051304:Profilins; D014443:Tyrosine; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; C494469:VHL protein, mouse
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