美国德克萨斯大学Giannicola Genovese研究小组发现，上皮细胞向间质细胞转变的进化指纹。相关论文于2025年3月5日发表于国际顶尖学术期刊《自然》杂志上。

在这里，该研究组澄清了EMT对胰腺癌恶性进展的贡献。该研究团队以体细胞镶嵌基因组工程技术为主题，沿着EMT连续体追踪和切除恶性间充质谱系。实验证据阐明了间充质细胞系对胰腺癌进化的重要贡献。EMT的空间基因组分析、单细胞转录组学和表观基因组分析阐明了其对基因组不稳定性的贡献，包括染色体断裂事件的出现。胰腺和其他人类实体肿瘤的跨物种分析证实，间充质谱系的基因消融明显地消除了这些突变过程和进化模式。

在机制上，研究组发现具有间充质特征的恶性细胞显示出染色质可及性增加，特别是在着丝粒周围和着丝粒区域，进而导致有丝分裂延迟和灾难性细胞分裂。因此，EMT有利于基因组不稳定、高度适应的肿瘤细胞的出现，这有力地支持了细胞状态限制进化模式的概念，即癌细胞物种在受限制的功能区室中传播给后代。通过消除具有间充质可塑性的克隆和消除衍生谱系来抑制进化途径，可以阻止人类癌症中最具侵袭性的一种形式的恶性潜能。

据介绍，间充质可塑性在晚期上皮癌中被广泛描述；然而，它在恶性进展中的功能作用是有争议的。上皮-间质转化（EMT）和细胞可塑性在肿瘤异质性和克隆进化中的作用尚不清楚。

附：英文原文

Title: Evolutionary fingerprints of epithelial-to-mesenchymal transition

Author: Perelli, Luigi, Zhang, Li, Mangiameli, Sarah, Giannese, Francesca, Mahadevan, Krishnan K., Peng, Fuduan, Citron, Francesca, Khan, Hania, Le, Courtney, Gurreri, Enrico, Carbone, Federica, Russell, Andrew J. C., Soeung, Melinda, Lam, Truong Nguyen Anh, Lundgren, Sebastian, Marisetty, Sujay, Zhu, Cihui, Catania, Desiree, Mohamed, Alaa M. T., Feng, Ningping, Augustine, Jithesh Jose, Sgambato, Alessandro, Tortora, Giampaolo, Draetta, Giulio F., Tonon, Giovanni, Futreal, Andrew, Giuliani, Virginia, Carugo, Alessandro, Viale, Andrea, Kim, Michael P., Heffernan, Timothy P., Wang, Linghua, Kalluri, Raghu, Cittaro, Davide, Chen, Fei, Genovese, Giannicola

Issue&Volume: 2025-03-05

Abstract: Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1,2,3,4,5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.

DOI: 10.1038/s41586-025-08671-2

Source: https://www.nature.com/articles/s41586-025-08671-2