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.