Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner
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 mel...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-05-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/5/1297 |
| _version_ | 1797567359251120128 |
|---|---|
| author | Manale El Kharbili Muriel Cario Nicolas Béchetoille Catherine Pain Claude Boucheix Françoise Degoul Ingrid Masse Odile Berthier-Vergnes |
| author_facet | Manale El Kharbili Muriel Cario Nicolas Béchetoille Catherine Pain Claude Boucheix Françoise Degoul Ingrid Masse Odile Berthier-Vergnes |
| author_sort | Manale El Kharbili |
| collection | DOAJ |
| description | 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’ translocation to the dermis. Mechanistically, Tspan8<sup>+</sup> 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. |
| first_indexed | 2024-03-10T19:41:41Z |
| format | Article |
| id | doaj.art-57b79f9540c74fd8923d257a6096e1a7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:41:41Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-57b79f9540c74fd8923d257a6096e1a72023-11-20T01:12:15ZengMDPI AGCancers2072-66942020-05-01125129710.3390/cancers12051297Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent MannerManale El Kharbili0Muriel Cario1Nicolas Béchetoille2Catherine Pain3Claude Boucheix4Françoise Degoul5Ingrid Masse6Odile Berthier-Vergnes7Centre de Génétique et de Physiologie Moléculaires et Cellulaires, CNRS UMR5534, Université de Lyon, F-69003 Lyon, FranceNational Reference Center for Rare Skin Disease, Department of Dermatology, University Hospital, INSERM 1035, F-33000 Bordeaux, FranceR&D Department, Gattefossé, F-69800 Saint-Priest, FranceNational Reference Center for Rare Skin Disease, Department of Dermatology, University Hospital, INSERM 1035, F-33000 Bordeaux, FranceINSERM U935, Université Paris-Sud, F-94800 Villejuif, FranceINSERM U1240, Université Clermont Auvergne, Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont Ferrand, FranceCentre de Génétique et de Physiologie Moléculaires et Cellulaires, CNRS UMR5534, Université de Lyon, F-69003 Lyon, FranceCentre de Génétique et de Physiologie Moléculaires et Cellulaires, CNRS UMR5534, Université de Lyon, F-69003 Lyon, FranceMelanoma 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’ translocation to the dermis. Mechanistically, Tspan8<sup>+</sup> 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.https://www.mdpi.com/2072-6694/12/5/1297tumor microenvironmentmelanoma invasionmelanoma-keratinocytes crosstalkdermal-epidermal junctiondermisTetraspanin 8 |
| spellingShingle | Manale El Kharbili Muriel Cario Nicolas Béchetoille Catherine Pain Claude Boucheix Françoise Degoul Ingrid Masse Odile Berthier-Vergnes Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner Cancers tumor microenvironment melanoma invasion melanoma-keratinocytes crosstalk dermal-epidermal junction dermis Tetraspanin 8 |
| title | Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner |
| title_full | Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner |
| title_fullStr | Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner |
| title_full_unstemmed | Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner |
| title_short | Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner |
| title_sort | tspan8 drives melanoma dermal invasion by promoting prommp 9 activation and basement membrane proteolysis in a keratinocyte dependent manner |
| topic | tumor microenvironment melanoma invasion melanoma-keratinocytes crosstalk dermal-epidermal junction dermis Tetraspanin 8 |
| url | https://www.mdpi.com/2072-6694/12/5/1297 |
| work_keys_str_mv | AT manaleelkharbili tspan8drivesmelanomadermalinvasionbypromotingprommp9activationandbasementmembraneproteolysisinakeratinocytedependentmanner AT murielcario tspan8drivesmelanomadermalinvasionbypromotingprommp9activationandbasementmembraneproteolysisinakeratinocytedependentmanner AT nicolasbechetoille tspan8drivesmelanomadermalinvasionbypromotingprommp9activationandbasementmembraneproteolysisinakeratinocytedependentmanner AT catherinepain tspan8drivesmelanomadermalinvasionbypromotingprommp9activationandbasementmembraneproteolysisinakeratinocytedependentmanner AT claudeboucheix tspan8drivesmelanomadermalinvasionbypromotingprommp9activationandbasementmembraneproteolysisinakeratinocytedependentmanner AT francoisedegoul tspan8drivesmelanomadermalinvasionbypromotingprommp9activationandbasementmembraneproteolysisinakeratinocytedependentmanner AT ingridmasse tspan8drivesmelanomadermalinvasionbypromotingprommp9activationandbasementmembraneproteolysisinakeratinocytedependentmanner AT odileberthiervergnes tspan8drivesmelanomadermalinvasionbypromotingprommp9activationandbasementmembraneproteolysisinakeratinocytedependentmanner |