Lysosomal acid ceramidase ASAH1 controls the transition between invasive and proliferative phenotype in melanoma cells

Abstract

Phenotypic plasticity and subsequent generation of intratumoral heterogeneity underly key traits in malignant melanoma such as drug resistance and metastasis. Melanoma plasticity promotes a switch between proliferative and invasive phenotypes characterized by different transcriptional programs of which MITF is a critical regulator. Here, we show that the acid ceramidase ASAH1, which controls sphingolipid metabolism, acted as a rheostat of the phenotypic switch in melanoma cells. Low ASAH1 expression was associated with an invasive behavior mediated by activation of the integrin alphavbeta5-FAK signaling cascade. In line with that, human melanoma biopsies revealed heterogeneous staining of ASAH1 and low ASAH1 expression at the melanoma invasive front. We also identified ASAH1 as a new target of MITF, thereby involving MITF in the regulation of sphingolipid metabolism. Together, our findings provide new cues to the mechanisms underlying the phenotypic plasticity of melanoma cells and identify new anti-metastatic targets.

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Acknowledgements

This work was supported by Inserm, La Société Française de Dermatologie, and by a grant from INCA (INCA_10573). CP is a fellowship from la Ligue Nationale contre le Cancer. The authors thank Dr. M Sewer (San Diego, USA) for providing the ASAH1 promoter vector. WM3912, WM8, WM3928 and WM3918 human melanoma cell lines were a kind gift from H Meenhard and G Zhang (Wistar melanoma Institute, Philadelphia, USA).

Author contributions

CB, NA-A, RB and TL designed the research, analyzed the results and wrote the manuscript. GT, SD, JC and PB performed and analyzed the immunohistochemistry experiments. NN performed the bioinformatics analysis. JL, DG, CP, CG, KB, VG, PC, SP and BM performed all the other experiments.

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Correspondence to Corine Bertolotto.

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Leclerc, J., Garandeau, D., Pandiani, C. et al. Lysosomal acid ceramidase ASAH1 controls the transition between invasive and proliferative phenotype in melanoma cells. Oncogene 38, 1282–1295 (2019). https://doi.org/10.1038/s41388-018-0500-0

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