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Tspan8-β-catenin positive feedback loop promotes melanoma invasion

Oncogene volume 38, pages 3781–3793 (2019)Cite this article

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Abstract

Due to its high proclivity to metastasize, and despite the recent development of targeted and immune therapy strategies, melanoma is still the deadliest form of skin cancer. Therefore, understanding the molecular mechanisms underlying melanoma invasion remains crucial. We previously characterized Tspan8 for its ability to prompt melanoma cell detachment from their microenvironment and trigger melanoma cell invasiveness, but the signaling events by which Tspan8 regulates the invasion process still remain unknown. Here, we demonstrated that β-catenin stabilization is a molecular signal subsequent to the onset of Tspan8 expression, and that, in turn, β-catenin triggers the direct transcriptional activation of Tspan8 expression, leading to melanoma invasion. Moreover, we showed that β-catenin activation systematically correlates with a high expression of Tspan8 protein in melanoma lesions from transgenic Nras; bcat* mice, as well as in deep penetrating naevi, a type of human pre-melanoma neoplasm characterized by a combined activation of β-catenin and MAP kinase signaling. Overall, our data suggest that β-catenin and Tspan8 are part of a positive feedback loop, which sustains a high Tspan8 expression level, conferring to melanoma cells the invasive properties required for tumor progression and dissemination.

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Acknowledgements

We thank Elise Malandain for technical assistance and Cyril Py for immunohistochemical processing. We thank C. Boucheix for the gift of TS29 monoclonal antibody.

Author contributions

IM and OBV conceived the idea and designed research. MEL, GA, LBB, OBV and IM performed experimental research. MEL, GA and LBB analyzed data under the supervision of IM and OBV. RMP performed bioinformatics analysis. ADLF provided tumor specimens and performed immunohistochemistry analyzes. LL performed mouse experiments. MEL, GA, JC and AP were involved in critical revision of the manuscript. IM and OBV prepared figures and wrote the paper.

Funding

This work was supported by a grant from the French Society for Dermatological Research (SRD), a grant from La Ligue Contre le Cancer (Comité Ardèche) and a grant from the association “Vaincre le Mélanome”.

Author information

Author notes

  1. Manale El Kharbili

    Present address: Department of Dermatology, University of Colorado Anschutz Medical Campus, 12800 E. 19th Avenue, P18-8132, Aurora, CO, 80045, USA

  2. Laetitia Barbollat-Boutrand & Ingrid Masse

    Present address: Centre de Recherche en Cancérologie de Lyon, CNRS UMR5286, Inserm U1052, Université de Lyon, Université Lyon 1, 69000, Lyon, France

  3. These authors contributed equally: Manale El Kharbili and Gweltaz Agaësse

  4. These authors contributed equally: Odile Berthier-Vergnes and Ingrid Masse

Authors and Affiliations

  1. Université de Lyon, F-69003, Lyon, France

    Manale El Kharbili, Gweltaz Agaësse, Laetitia Barbollat-Boutrand, Odile Berthier-Vergnes & Ingrid Masse

  2. Université Lyon 1, Lyon, F-69003, France

    Manale El Kharbili, Gweltaz Agaësse, Laetitia Barbollat-Boutrand, Odile Berthier-Vergnes & Ingrid Masse

  3. CNRS, UMR5534, Centre de Génétique et de Physiologie Moléculaires et Cellulaires, Villeurbanne, F-69622, France

    Manale El Kharbili, Gweltaz Agaësse, Laetitia Barbollat-Boutrand, Odile Berthier-Vergnes & Ingrid Masse

  4. Centre de Recherche en Cancérologie de Lyon, CNRS UMR5286, Inserm U1052, Université de Lyon, Université Lyon 1, 69000, Lyon, France

    Roxane M. Pommier, Arnaud de la Fouchardière, Julie Caramel & Alain Puisieux

  5. Département de Biopathologie, Centre Leon Bérard, Lyon, France

    Arnaud de la Fouchardière

  6. Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, Orsay, France

    Lionel Larue

  7. Univ Paris-Sud, Univ Paris-Saclay, CNRS UMR 3347, Orsay, France

    Lionel Larue

  8. Equipe Labellisée Ligue Contre le Cancer, Orsay, France

    Lionel Larue

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El Kharbili, M., Agaësse, G., Barbollat-Boutrand, L. et al. Tspan8-β-catenin positive feedback loop promotes melanoma invasion. Oncogene 38, 3781–3793 (2019). https://doi.org/10.1038/s41388-019-0691-z

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