Epithelial–mesenchymal transition (EMT) programs operate within carcinoma cells, where they generate phenotypes associated with malignant progression. In their various manifestations, EMT programs enable epithelial cells to enter into a series of intermediate states arrayed along the E–M phenotypic spectrum. At present, we lack a coherent understanding of how carcinoma cells control their entrance into and continued residence in these various states, and which of these states favour the process of metastasis. Here we characterize a layer of EMT-regulating machinery that governs E–M plasticity (EMP). This machinery consists of two chromatin-modifying complexes, PRC2 and KMT2D-COMPASS, which operate as critical regulators to maintain a stable epithelial state. Interestingly, loss of these two complexes unlocks two distinct EMT trajectories. Dysfunction of PRC2, but not KMT2D-COMPASS, yields a quasi-mesenchymal state that is associated with highly metastatic capabilities and poor survival of patients with breast cancer, suggesting that great caution should be applied when PRC2 inhibitors are evaluated clinically in certain patient cohorts. These observations identify epigenetic factors that regulate EMP, determine specific intermediate EMT states and, as a direct consequence, govern the metastatic ability of carcinoma cells.

上皮 - 间质转化（EMT）程序在癌细胞内运作，在那里它们产生与恶性进展相关的表型。在其各种表现中，EMT 程序使上皮细胞能够进入一系列沿 E-M 表型谱排列的中间状态。目前，我们对癌细胞如何控制它们进入这些不同状态并继续驻留以及这些状态中的哪些有利于转移过程缺乏一致的理解。在这里，我们描述了一层控制 E-M 可塑性 (EMP) 的 EMT 调节机制。该机器由两个染色质修饰复合物PRC2和KMT2D-COMPASS组成，它们作为关键调节剂发挥作用以维持稳定的上皮状态。有趣的是，这两个复合物的丢失解锁了两条不同的 EMT 轨迹。PRC2 的功能障碍，但不是 KMT2D-COMPASS，会产生一种准间充质状态，这种状态与乳腺癌患者的高转移能力和较差的生存率有关，这表明在某些患者队列中对 PRC2 抑制剂进行临床评估时应非常谨慎。这些观察结果确定了调节 EMP 的表观遗传因素，确定特定的中间 EMT 状态，并作为直接结果控制癌细胞的转移能力。