Oncotarget

Research Papers:

Tetraspanin 8 is a novel regulator of ILK-driven β1 integrin adhesion and signaling in invasive melanoma cells

Manale El Kharbili, Clement Robert, Tiffany Witkowski, Emmanuelle Danty-Berger, Laetitia Barbollat-Boutrand, Ingrid Masse, Nicolas Gadot, Arnaud de la Fouchardiere, Paul C. McDonald, Shoukat Dedhar, Francois Le Naour, Francoise Degoul, Odile Berthier-Vergnes _

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Oncotarget. 2017; 8:17140-17155. doi: 10.18632/oncotarget.15084

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Abstract

Manale El Kharbili1,2,3,4, Clément Robert1,2,3, Tiffany Witkowski5,6, Emmanuelle Danty-Berger7, Laetitia Barbollat-Boutrand1,2,3, Ingrid Masse1,2,3, Nicolas Gadot8, Arnaud de la Fouchardière9, Paul C. McDonald10, Shoukat Dedhar10, François Le Naour11,12, Françoise Degoul5,6, Odile Berthier-Vergnes1,2,3

1Université de Lyon, Lyon, France

2Université Lyon 1, Lyon, France

3CNRS, UMR5534, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Villeurbanne, France

4Current address: Department of Dermatology, University of Colorado, Aurora, Colorado, USA

5Clermont Université, Université d’Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France

6Inserm, U990, Clermont-Ferrand, France

7Laboratoire CarMeN (INSERM 1060, INRA1397, INSA), Université Lyon 1, Lyon, France

8Université Lyon 1, Fédération de Recherche Santé Lyon-Est, ANIPATH, Faculté Laennec, Lyon, France

9Département de Biopathologie, Centre Léon Bérard, Lyon, France

10Department of Integrative Oncology, British Columbia Cancer Research Center, Vancouver, Canada

11INSERM U602, Villejuif, France

12Current address: INSERM U1193, Hôpital Paul Brousse, Villejuif, France

Correspondence to:

Odile Berthier-Vergnes, email: odile.berthier-vergnes@univ-lyon1.fr

Keywords: melanoma, matrix, integrin, tetraspanin 8, ILK

Received: November 09, 2016     Accepted: January 09, 2017     Published: February 04, 2017

ABSTRACT

Melanoma is well known for its propensity for lethal metastasis and resistance to most current therapies. Tumor progression and drug resistance depend to a large extent on the interplay between tumor cells and the surrounding matrix. We previously identified Tetraspanin 8 (Tspan8) as a critical mediator of melanoma invasion, whose expression is absent in healthy skin. The present study investigated whether Tspan8 may influence cell-matrix anchorage and regulate downstream molecular pathways leading to an aggressive behavior. Using silencing and ectopic expression strategies, we showed that Tspan8-mediated invasion of melanoma cells resulted from defects in cell-matrix anchorage by interacting with β1 integrins and by interfering with their clustering, without affecting their surface or global expression levels. These effects were associated with impaired phosphorylation of integrin-linked kinase (ILK) and its downstream target Akt-S473, but not FAK. Specific blockade of Akt or ILK activity strongly affected cell-matrix adhesion. Moreover, expression of a dominant-negative form of ILK reduced β1 integrin clustering and cell-matrix adhesion. Finally, we observed a tumor-promoting effect of Tspan8 in vivo and a mutually exclusive expression pattern between Tspan8 and phosphorylated ILK in melanoma xenografts and human melanocytic lesions. Altogether, the in vitro, in vivo and in situ data highlight a novel regulatory role for Tspan8 in melanoma progression by modulating cell-matrix interactions through β1 integrin-ILK axis and establish Tspan8 as a negative regulator of ILK activity. These findings emphasize the importance of targeting Tspan8 as a means of switching from low- to firm-adhesive states, mandatory to prevent tumor dissemination.

Author Information

Manale El Kharbili

Clement Robert

Tiffany Witkowski

Emmanuelle Danty-Berger

Laetitia Barbollat-Boutrand

Ingrid Masse

Nicolas Gadot

Arnaud de la Fouchardiere

Paul C. McDonald

Shoukat Dedhar

Francois Le Naour

Francoise Degoul

Odile Berthier-Vergnes
Primary Contact  _


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