Evolutionary fingerprints of epithelial-to-mesenchymal transition

Luigi Perelli (), Li Zhang, Sarah Mangiameli, Francesca Giannese, Krishnan K. Mahadevan, Fuduan Peng, Francesca Citron, Hania Khan, Courtney Le, Enrico Gurreri, Federica Carbone, Andrew J. C. Russell, Melinda Soeung, Truong Nguyen Anh Lam, Sebastian Lundgren, Sujay Marisetty, Cihui Zhu, Desiree Catania, Alaa M. T. Mohamed, Ningping Feng, Jithesh Jose Augustine, Alessandro Sgambato, Giampaolo Tortora, Giulio F. Draetta, Giovanni Tonon, Andrew Futreal, Virginia Giuliani, Alessandro Carugo, Andrea Viale, Michael P. Kim, Timothy P. Heffernan, Linghua Wang, Raghu Kalluri, Davide Cittaro (), Fei Chen () and Giannicola Genovese ()
Additional contact information
Luigi Perelli: The University of Texas MD Anderson Cancer Center
Li Zhang: The University of Texas MD Anderson Cancer Center
Sarah Mangiameli: Broad Institute of Harvard and MIT
Francesca Giannese: IRCCS San Raffaele Institute
Krishnan K. Mahadevan: University of Texas MD Anderson Cancer Center
Fuduan Peng: The University of Texas MD Anderson Cancer Center
Francesca Citron: The University of Texas MD Anderson Cancer Center
Hania Khan: The University of Texas MD Anderson Cancer Center
Courtney Le: The University of Texas MD Anderson Cancer Center
Enrico Gurreri: The University of Texas MD Anderson Cancer Center
Federica Carbone: NMS Group
Andrew J. C. Russell: Broad Institute of Harvard and MIT
Melinda Soeung: The University of Texas MD Anderson Cancer Center
Truong Nguyen Anh Lam: The University of Texas MD Anderson Cancer Center
Sebastian Lundgren: The University of Texas MD Anderson Cancer Center
Sujay Marisetty: The University of Texas MD Anderson Cancer Center
Cihui Zhu: The University of Texas MD Anderson Cancer Center
Desiree Catania: The University of Texas MD Anderson Cancer Center
Alaa M. T. Mohamed: The University of Texas MD Anderson Cancer Center
Ningping Feng: The University of Texas MD Anderson Cancer Center
Jithesh Jose Augustine: The University of Texas MD Anderson Cancer Center
Alessandro Sgambato: Università Cattolica del Sacro Cuore
Giampaolo Tortora: Università Cattolica del Sacro Cuore
Giulio F. Draetta: The University of Texas MD Anderson Cancer Center
Giovanni Tonon: IRCCS San Raffaele Institute
Andrew Futreal: The University of Texas MD Anderson Cancer Center
Virginia Giuliani: The University of Texas MD Anderson Cancer Center
Alessandro Carugo: IRBM
Andrea Viale: The University of Texas MD Anderson Cancer Center
Michael P. Kim: The University of Texas MD Anderson Cancer Center
Timothy P. Heffernan: The University of Texas MD Anderson Cancer Center
Linghua Wang: The University of Texas MD Anderson Cancer Center
Raghu Kalluri: University of Texas MD Anderson Cancer Center
Davide Cittaro: IRCCS San Raffaele Institute
Fei Chen: Broad Institute of Harvard and MIT
Giannicola Genovese: The University of Texas MD Anderson Cancer Center

Nature, 2025, vol. 640, issue 8060, 1083-1092

Abstract: Abstract Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1–5. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08671-2

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