表观遗传调控机制使得多细胞生物能够在拥有相同基因组的条件下，发展出不同的细胞特化身份。细胞命运决定于基因表达计划和细胞在胚胎发育过程中经历的环境刺激，并通常在生物整个寿命中保持，即使面临新的环境刺激。进化上保守的Polycomb群蛋白(PcG)形成Polycomb抑制复合物，帮助协调这些发育选择。发育后，这些复合物积极维持产生的细胞命运，即使面临环境扰动。鉴于这些Polycomb机制在提供表型稳定性方面的关键作用，即维持细胞命运不变，我们假设它们在发育后的失调会导致表型稳定性降低，从而使失调的细胞可以持续地在环境变化的情况下切换其表型，称之为异常表型转换现象。我们引入了一种通用的计算进化模型，可以在无特定背景下检验我们的系统级表型可塑性假设。我们发现：1）表型稳定性是PcG样机制演化的一种新兴系统级属性；2）表型可塑性是这个机制失调后产生的一种新兴系统级属性。由于有证据表明转移性癌细胞表现出表型可塑性，我们假设肿瘤细胞的表型可塑性是由于PcG机制失调而导致的，从而推动了癌细胞向转移的进展。我们利用来自转移性癌症的单细胞RNA测序数据验证了我们的假设。我们发现，转移性癌细胞的表型可塑性与我们的模型预测的方式相同。版权： ©2023 Lambros等人。本文为开放获取文章，依照知识共享署名许可协议，允许任何人以任何方式使用、分发和再利用本文，但需注明原作者和出处。

Epigenetic regulatory mechanisms allow multicellular organisms to develop distinct specialized cell identities despite having the same total genome. Cell-fate choices are based on gene expression programs and environmental cues that cells experience during embryonic development, and are usually maintained throughout the life of the organism despite new environmental cues. The evolutionarily conserved Polycomb group (PcG) proteins form Polycomb Repressive Complexes that help orchestrate these developmental choices. Post-development, these complexes actively maintain the resulting cell fate, even in the face of environmental perturbations. Given the crucial role of these polycomb mechanisms in providing phenotypic fidelity (i.e. maintenance of cell fate), we hypothesize that their dysregulation after development will lead to decreased phenotypic fidelity allowing dysregulated cells to sustainably switch their phenotype in response to environmental changes. We call this abnormal phenotypic switching phenotypic pliancy. We introduce a general computational evolutionary model that allows us to test our systems-level phenotypic pliancy hypothesis in-silico and in a context-independent manner. We find that 1) phenotypic fidelity is an emergent systems-level property of PcG-like mechanism evolution, and 2) phenotypic pliancy is an emergent systems-level property resulting from this mechanism's dysregulation. Since there is evidence that metastatic cells behave in a phenotypically pliant manner, we hypothesize that progression to metastasis is driven by the emergence of phenotypic pliancy in cancer cells as a result of PcG mechanism dysregulation. We corroborate our hypothesis using single-cell RNA-sequencing data from metastatic cancers. We find that metastatic cancer cells are phenotypically pliant in the same manner as predicted by our model.Copyright: © 2023 Lambros et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.