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.

中文翻译：

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溶酶体酸性神经酰胺酶 ASAH1 控制黑色素瘤细胞侵袭性和增殖性表型之间的转变。

表型可塑性和随后产生的瘤内异质性是恶性黑色素瘤的关键特征，例如耐药性和转移。黑色素瘤可塑性促进增殖性和侵袭性表型之间的转换，其特征是不同的转录程序，其中 MITF 是一个关键的调节因子。在这里，我们表明控制鞘脂代谢的酸性神经酰胺酶 ASAH1 在黑色素瘤细胞中充当表型转换的变阻器。低 ASAH1 表达与激活整合素 alphavbeta5-FAK 信号级联介导的侵入性行为相关。与此一致，人类黑色素瘤活检显示在黑色素瘤侵袭前沿处 ASAH1 的异质染色和低 ASAH1 表达。我们还将 ASAH1 确定为 MITF 的新目标，从而使 MITF 参与调节鞘脂代谢。总之，我们的研究结果为黑色素瘤细胞表型可塑性的潜在机制提供了新线索，并确定了新的抗转移靶点。