Evolutionary fingerprints of epithelial-to-mesenchymal transition

• 成果类型: Article
• 署名作者: 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
• 署名单位: University of Texas System; UTMD Anderson Cancer Center; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli; Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli; Nerviano Medical Sciences S.r.l; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli; Merck & Company; Merck & Company Italy; University of Texas System; UTMD Anderson Cancer Center; Rice University; Baylor College of Medicine; University of Texas System; UTMD Anderson Cancer Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3526
• DOI: 10.1038/s41586-025-08671-2
• 发表日期: 2025-04-24
• 关键词: pancreatic-cancer; tumor; emt; metastasis; chemoresistance; quantification; plasticity; hallmarks; responses; subtypes

摘要

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.