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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Tetraspanin8 expression predicts an increased metastatic risk and is associated with cancer-related death in human cutaneous melanoma
Molecular Cancer Open Access 02 October 2021
Oncogene Open Access 23 June 2021
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We thank Elise Malandain for technical assistance and Cyril Py for immunohistochemical processing. We thank C. Boucheix for the gift of TS29 monoclonal antibody.
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.
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”.
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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