Temporal activation of WNT/\u03b2-catenin signaling is sufficient to inhibit SOX10 expression and block melanoma growth

Rexhep Uka,Mitchell P Levesque,Michal J Okoniewski,Paolo Cinelli,Olga Shakhova,Daniela Mihic,Roger Stupp,Marco Gualandi,Christian Britschgi,Reinhard Dummer,Claudia Matter,Anja Krättli

doi:10.1038/s41388-020-1267-7

Abstract

Despite advances in the systemic treatment of patients with metastatic melanoma using immune checkpoint and tyrosine kinase inhibitors (TKI), the majority of stage IV melanoma patients eventually succumb to the disease. We have previously identified the transcription factor Sox10 as a crucial player in melanoma, yet the underlying molecular mechanisms mediating Sox10-dependent tumorigenesis remain largely uncharacterized. Here, we show that MEK and RAF inhibitors do not suppress levels of SOX10 protein in patient-derived cells in vitro, as well as in melanoma patients in vivo. In a search for pharmacological inhibitors of SOX10, we performed a mass spectrometry-based screen in human melanoma cells. Subsequent analysis revealed that SOX10 directly interacts with β-catenin, which is a key mediator of canonical Wnt/β-catenin signaling. We demonstrate that inhibitors of glycogen synthase kinase 3 alpha/beta (GSK3α/β) efficiently abrogate SOX10 protein in human melanoma cells in vitro and in melanoma mouse models in vivo. The mechanism of action of GSK3-mediated SOX10 suppression is transcription-independent and relies on the presence of a proteasome degradable form of β-catenin. Taken together, we provide evidence that activation of canonical Wnt signaling has a profound effect on melanoma growth and is able to counteract Sox10-dependent melanoma maintenance both in vitro and in vivo.

Highlights

Melanoma is the most aggressive type of skin cancer, characterized by highly invasive and metastatic features
We have previously shown that SOX10 is expressed in one hundred percent of primary human melanoma samples and that its expression is crucial for melanoma initiation, and maintenance of established melanomas [8]
Given the clinical observation that the majority of patients treated with small molecule inhibitors against BRAF or MEK kinases will eventually relapse, we investigated the capacity of those agents to suppress SOX10 expression in vivo and in vitro [2, 5, 6]

Summary

Introduction

Melanoma is the most aggressive type of skin cancer, characterized by highly invasive and metastatic features. Major risk factors are genetic predisposition and exposure to ultraviolet radiation, and the incidence of melanoma continues to increase worldwide [1]. While patients with early stage melanoma can often be cured by surgical intervention, patients with metastatic disease have a very poor prognosis. Despite recent significant advances in systemic treatment of metastatic melanoma, including targeted therapies and immune checkpoint inhibitors, which might even lead to cure in some patients, metastatic melanoma remains a deadly disease for the majority, since they will eventually develop resistance to these approaches [2,3,4,5,6,7]. We have previously demonstrated that Sox, a neural crest transcription factor, plays a crucial role in the development and maintenance of giant congenital melanocytic nevi and melanoma [8]

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Conclusion