title: Endothelial podosome rosettes regulate vascular branching in tumour angiogenesis.
abstract: The mechanism by which angiogenic endothelial cells break the physical barrier of the vascular basement membrane and consequently sprout to form new vessels in mature tissues is unclear. Here, we show that the angiogenic endothelium is characterized by the presence of functional podosome rosettes. These extracellular-matrix-degrading and adhesive structures are precursors of de novo branching points and represent a key feature in the formation of new blood vessels. VEGF-A stimulation induces the formation of endothelial podosome rosettes by upregulating integrin α6β1. In contrast, the binding of α6β1 integrin to the laminin of the vascular basement membrane impairs the formation of podosome rosettes by restricting α6β1 integrin to focal adhesions and hampering its translocation to podosomes. Using an ex vivo sprouting angiogenesis assay, transgenic and knockout mouse models and human tumour sample analysis, we provide evidence that endothelial podosome rosettes control blood vessel branching and are critical regulators of pathological angiogenesis.
authors.affiliation: 1] Department of Oncology, University of Torino, Turin 10100, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy [3] Edwin L. Steele Laboratory for Tumor Biology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Seano
authors.affiliation: 1] Department of Oncology, University of Torino, Turin 10100, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Chiaverina
authors.affiliation: 1] Department of Oncology, University of Torino, Turin 10100, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy.
authors.forename: Paolo Armando
authors.initials: PA
authors.lastname: Gagliardi
authors.affiliation: 1] Department of Oncology, University of Torino, Turin 10100, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: di Blasio
authors.affiliation: 1] Department of Oncology, University of Torino, Turin 10100, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Puliafito
authors.affiliation: UMR-S 765, Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Bouvard
authors.affiliation: 1] Department of Oncology, University of Torino, Turin 10100, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sessa
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Molecular Biotechnology Center, Turin 10124, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, Muenster University, Muenster 48149, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Sorokin
authors.affiliation: UMR-S 970, Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Helley
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: 1] Department of Oncology, University of Torino, Turin 10100, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Serini
authors.affiliation: 1] Department of Oncology, University of Torino, Turin 10100, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.affiliation: 1] Department of Oncology, University of Torino, Turin 10100, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Primo
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D045744:Cell Line, Tumor; D021961:Cell Membrane Structures / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D039121:Integrin alpha6beta1 / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D034622:RNA Interference; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology
chemical_list: D039121:Integrin alpha6beta1; D007797:Laminin; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D053511:Matrix Metalloproteinase 14; D013755:Tetradecanoylphorbol Acetate