Tspan8-β-catenin positive feedback loop promotes melanoma invasion

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 Ts...

Full description

Saved in:
Bibliographic Details
Published in:Oncogene 2019-05, Vol.38 (20), p.3781-3793
Main Authors: El Kharbili, Manale, Agaësse, Gweltaz, Barbollat-Boutrand, Laetitia, Pommier, Roxane M, de la Fouchardière, Arnaud, Larue, Lionel, Caramel, Julie, Puisieux, Alain, Berthier-Vergnes, Odile, Masse, Ingrid
Format: Article
Language:English
Subjects:
Animals
beta Catenin - genetics
beta Catenin - metabolism
Feedback
Feedback, Physiological
Gene Expression Regulation, Neoplastic
Humans
Invasiveness
Kinases
Life Sciences
MAP kinase
Melanoma
Melanoma - genetics
Melanoma - metabolism
Melanoma - pathology
Melanoma, Cutaneous Malignant
Mice, Transgenic
Molecular modelling
Promoter Regions, Genetic
Protein Stability
Skin cancer
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Skin Neoplasms - pathology
Tetraspanins - genetics
Tetraspanins - metabolism
Transcription activation
Transgenic mice
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
β-catenin
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-019-0691-z