Malignant melanoma displays a high degree of cellular plasticity during disease progression. Signals in the tumor microenvironment are believed to influence melanoma plasticity through changes in the epigenetic state to guide dynamic differentiation and de-differentiation. Here we uncover a relationship between geometric features at perimeter regions of melanoma aggregates, and reprogramming to a stem cell-like state through histone marks H3K4Me2 and H3K9Ac. Using an in vitro tumor microengineering approach, we find spatial enrichment of these histone modifications with concurrent expression of stemness markers. The epigenetic modifier PRDM14 overlaps with H3K9Ac and shows elevated expression in cells along regions of perimeter curvature. siRNA knockdown of PRDM14 abolishes the MIC phenotype suggesting a role in regulating melanoma heterogeneity. Our results suggest mechanotransduction at the periphery of melanoma aggregates may orchestrate the activity of epigenetic modifiers to regulate histone state, cellular plasticity, and tumorigenicity.

恶性黑色素瘤在疾病进展过程中表现出高度的细胞可塑性。据信肿瘤微环境中的信号通过表观遗传状态的变化影响黑色素瘤可塑性，从而指导动态分化和去分化。在这里，我们揭示了黑色素瘤聚集体周围区域的几何特征之间的关系，并通过组蛋白标记H3K4Me2和H3K9Ac重新编程为干细胞状状态。使用体外肿瘤微工程学方法，我们发现这些组蛋白修饰的空间富集与干性标记的同时表达。表观遗传修饰剂PRDM14与H3K9Ac重叠，并在沿周边曲率区域的细胞中表达升高。PRDM14的siRNA敲低消除了MIC表型，表明在调节黑素瘤异质性中起作用。我们的结果表明，黑色素瘤聚集体外围的机械转导可能协调表观遗传修饰剂的活性，以调节组蛋白状态，细胞可塑性和致瘤性。