Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner
| Autor: | Kharbili, Manale El, Cario, Muriel, Béchetoille, Nicolas, Pain, Catherine, Boucheix, Claude, Degoul, Françoise, Masse, Ingrid, Berthier-Vergnes, Odile |
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| Přispěvatelé: | Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, National Reference Center for Rare Skin Disease, Department of Dermatology, University Hospital, INSERM 1035, F-33000 Bordeaux, AquiDerm, University Bordeaux, F-33076 Bordeaux, R&D Department, Gattefossé, F-69800 Saint-Priest, INSERM U935, Université Paris-Sud, F-94800 Villejuif, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Santé Lyon Est - Louis Léopold Ollier, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), COLO, Mouniati, Centre de Génétique et de Physiologie Moléculaires et Cellulaires, CNRS UMR5534, Université de Lyon, F-69003 Lyon, Centre de Recherche en Cancérologie de Lyon, CNRS-UMR5286, INSERM U1052, Université de Lyon, F-69008 Lyon, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
endocrine system
integumentary system [SDV]Life Sciences [q-bio] [SDV.CAN]Life Sciences [q-bio]/Cancer melanoma invasion lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Tetraspanin 8 lcsh:RC254-282 Article dermis [SDV] Life Sciences [q-bio] dermal-epidermal junction [SDV.CAN] Life Sciences [q-bio]/Cancer tumor microenvironment MMP-9 neoplasms melanoma-keratinocytes crosstalk |
| Zdroj: | Cancers Cancers, 2020, 12 (5), pp.1297. ⟨10.3390/cancers12051297⟩ Cancers, MDPI, 2020, 12 (5), pp.1297. ⟨10.3390/cancers12051297⟩ Cancers, Vol 12, Iss 1297, p 1297 (2020) Volume 12 Issue 5 |
| ISSN: | 2072-6694 |
| Popis: | Melanoma is the most aggressive skin cancer with an extremely challenging therapy. The dermal-epidermal junction (DEJ) degradation and subsequent dermal invasion are the earliest steps of melanoma dissemination, but the mechanisms remain elusive. We previously identified Tspan8 as a key actor in melanoma invasiveness. Here, we investigated Tspan8 mechanisms of action during dermal invasion, using a validated skin-reconstruct-model that recapitulates melanoma dermal penetration through an authentic DEJ. We demonstrate that Tspan8 is sufficient to induce melanoma cells&rsquo translocation to the dermis. Mechanistically, Tspan8+ melanoma cells cooperate with surrounding keratinocytes within the epidermis to promote keratinocyte-originated proMMP-9 activation process, collagen IV degradation and dermal colonization. This concurs with elevated active MMP-3 and low TIMP-1 levels, known to promote MMP-9 activity. Finally, a specific Tspan8-antibody reduces proMMP-9 activation and dermal invasion. Overall, our results provide new insights into the role of keratinocytes in melanoma dermal colonization through a cooperative mechanism never reported before, and establish for the first time the pro-invasive role of a tetraspanin family member in a cell non-autonomous manner. This work also displays solid arguments for the use of Tspan8-blocking antibodies to impede early melanoma spreading and therefore metastasis. |
| Databáze: | OpenAIRE |
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