title: Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1.
abstract: The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development.
authors.affiliation: The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. H.S. Raffaele Scientific Institute and Università Vita Salute San Raffaele, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mazzieri
authors.affiliation: H.S. Raffaele Scientific Institute and Università Vita Salute San Raffaele, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pietrogrande
authors.affiliation: H.S. Raffaele Scientific Institute and Università Vita Salute San Raffaele, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gerasi
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gandelli
authors.affiliation: Department of Pathology, Humanitas Research Hospital, IRCCS, Milan, Italy.
authors.forename: Piergiuseppe
authors.initials: P
authors.lastname: Colombo
authors.affiliation: The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. H.S. Raffaele Scientific Institute and Università Vita Salute San Raffaele, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Moi
authors.affiliation: CUSSB-University Center of Statistics for Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Brombin
authors.affiliation: CUSSB-University Center of Statistics for Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ambrosi
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.affiliation: Departments of Medicine and Cell Biology, New York University School of Medicine, New York, New York.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mignatti
authors.affiliation: IFOM (Fondazione Istituto FIRC di Oncologia Molecolare), Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy. Silvia.Dalessio@humanitasresearch.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Alessio
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology*; D061346:Laser Capture Microdissection; D021962:Membrane Microdomains; D051379:Mice; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D051881:Receptor, Notch1; D055293:Receptors, Urokinase Plasminogen Activator