The microphthalmia associated transcription factor (MITF) is a critical regulator of melanocyte development and differentiation. It also plays an important role in melanoma where it has been described as a molecular rheostat that, depending on activity levels, allows reversible switching between different cellular states. Here we show that MITF directly represses the expression of genes associated with the extracellular matrix (ECM) and focal adhesion pathways in human melanoma cells as well as of regulators of epithelial to mesenchymal transition (EMT) such as CDH2, thus affecting cell morphology and cell-matrix interactions. Importantly, we show that these effects of MITF are reversible, as expected from the rheostat model. The number of focal adhesion points increased upon MITF knockdown, a feature observed in drug resistant melanomas. Cells lacking MITF are similar to the cells of minimal residual disease observed in both human and zebrafish melanomas. Our results suggest that MITF plays a critical role as a repressor of gene expression and is actively involved in shaping the microenvironment of melanoma cells in a cell-autonomous manner.

中文翻译：

---

MITF 重新编程黑色素瘤中的细胞外基质和粘着斑

小眼相关转录因子 (MITF) 是黑素细胞发育和分化的关键调节因子。它在黑色素瘤中也起着重要作用，它被描述为一种分子变阻器，根据活性水平，它允许在不同细胞状态之间进行可逆转换。在这里，我们表明 MITF 直接抑制与人黑色素瘤细胞中的细胞外基质 (ECM) 和粘着斑通路相关的基因的表达，以及 CDH2 等上皮间质转化 (EMT) 调节因子的表达，从而影响细胞形态和细胞-矩阵交互。重要的是，我们表明 MITF 的这些影响是可逆的，正如变阻器模型所预期的那样。MITF 敲除后粘着斑的数量增加，这是在耐药黑色素瘤中观察到的特征。缺乏 MITF 的细胞与在人和斑马鱼黑色素瘤中观察到的微小残留病细胞相似。我们的研究结果表明，MITF 作为基因表达的抑制因子发挥着关键作用，并以细胞自主的方式积极参与塑造黑色素瘤细胞的微环境。