Urokinase receptor promotes skin tumor formation by preventing epithelial cell activation of Notch1

Roberta Mazzieri, Giovanni Pietrogrande, Laura Gerasi, Alessandro Gandelli, Piergiuseppe Colombo, Davide Moi, Chiara Brombin, Alessandro Ambrosi, Silvio Danese, Paolo Mignatti, Francesco Blasi, Silvia D'Alessio

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)4895-4909
Number of pages15
JournalCancer Research
Volume75
Issue number22
DOIs
Publication statusPublished - Nov 15 2015

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Urokinase Plasminogen Activator Receptors
Urokinase-Type Plasminogen Activator
Epithelial Cells
Skin
Neoplasms
Carcinogenesis
Keratoacanthoma
Papilloma
Skin Neoplasms
Keratinocytes
Homeostasis
Cell Proliferation
Lipids

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Urokinase receptor promotes skin tumor formation by preventing epithelial cell activation of Notch1. / Mazzieri, Roberta; Pietrogrande, Giovanni; Gerasi, Laura; Gandelli, Alessandro; Colombo, Piergiuseppe; Moi, Davide; Brombin, Chiara; Ambrosi, Alessandro; Danese, Silvio; Mignatti, Paolo; Blasi, Francesco; D'Alessio, Silvia.

In: Cancer Research, Vol. 75, No. 22, 15.11.2015, p. 4895-4909.

Research output: Contribution to journalArticle

Mazzieri, R, Pietrogrande, G, Gerasi, L, Gandelli, A, Colombo, P, Moi, D, Brombin, C, Ambrosi, A, Danese, S, Mignatti, P, Blasi, F & D'Alessio, S 2015, 'Urokinase receptor promotes skin tumor formation by preventing epithelial cell activation of Notch1', Cancer Research, vol. 75, no. 22, pp. 4895-4909. https://doi.org/10.1158/0008-5472.CAN-15-0378
Mazzieri, Roberta ; Pietrogrande, Giovanni ; Gerasi, Laura ; Gandelli, Alessandro ; Colombo, Piergiuseppe ; Moi, Davide ; Brombin, Chiara ; Ambrosi, Alessandro ; Danese, Silvio ; Mignatti, Paolo ; Blasi, Francesco ; D'Alessio, Silvia. / Urokinase receptor promotes skin tumor formation by preventing epithelial cell activation of Notch1. In: Cancer Research. 2015 ; Vol. 75, No. 22. pp. 4895-4909.
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