T-type calcium channels drive migration/invasion in BRAFV600E melanoma cells through Snail1

Melanoma is a malignant tumor derived from melanocytes. Once disseminated, it is usually highly resistant to chemotherapy and is associated with poor prognosis. We have recently reported that T-type calcium channels (TTCCs) are overexpressed in melanoma cells and play an important role in melanoma progression. Importantly, TTCC pharmacological blockers reduce proliferation and deregulate autophagy leading to apoptosis. Here, we analyze the role of autophagy during migration/invasion of melanoma cells. TTCC Cav3.1 and LC3-II proteins are highly expressed in BRAFV600E compared with NRAS mutant melanomas, both in cell lines and biopsies. Chloroquine, pharmacological blockade, or gene silencing of TTCCs inhibit the autophagic flux and impair the migration and invasion capabilities, specifically in BRAFV600E melanoma cells. Snail1 plays an important role in motility and invasion of melanoma cells. We show that Snail1 is strongly expressed in BRAFV600E melanoma cells and patient biopsies, and its expression decreases when autophagy is blocked. These results demonstrate a role of Snail1 during BRAFV600E melanoma progression and strongly suggest that targeting macroautophagy and, particularly TTCCs, might be a good therapeutic strategy to inhibit metastasis of the most common melanoma type (BRAFV600E). Supported by grants from ISCIII/FEDER “Una manera de hacer Europa” (FIS-PI1200260 and PI1500711 to RMM, PI1301980 to JH and CIBERONC-CB16/12/00231 to XMG), Fundació la Marató de TV3 (FMTV 201331-30 to SP, -31 to RMM, and -32 to AF), Generalitat de Catalunya (2014/SGR138 to XMG); and Cancer Research UK grants C33043/A12065 and C33043/A24478 (VSM, JLO). OM holds a predoctoral fellowship from IRBLleida/Diputació de Lleida and CB a predoctoral fellowship from University of Lleida. AM holds a postdoctoral fellowship from AECC Scientific Foundation. IRH is supported by Marie Sklodowska-Curie Action (H2020-MSCA-IF-2014-EF-ST). Tumor samples were obtained with the support of Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d'Oncologia de Catalunya (XBTC) and IRBLleida Biobank (B.0000682) and PLATAFORMA BIOBANCOS (PT17/0015/0027).