2. Academic Validation
  3. Evolutionary fingerprints of epithelial-to-mesenchymal transition

Evolutionary fingerprints of epithelial-to-mesenchymal transition

  • Nature. 2025 Apr;640(8060):1083-1092. doi: 10.1038/s41586-025-08671-2.
Luigi Perelli # 1,  Li Zhang # 2,  Sarah Mangiameli 3 4,  Francesca Giannese 5,  Krishnan K Mahadevan 6,  Fuduan Peng 7,  Francesca Citron 7,  Hania Khan 2,  Courtney Le 2,  Enrico Gurreri 2 8 9,  Federica Carbone 10,  Andrew J C Russell 3 4,  Melinda Soeung 7,  Truong Nguyen Anh Lam 2,  Sebastian Lundgren 2,  Sujay Marisetty 2,  Cihui Zhu 2,  Desiree Catania 11,  Alaa M T Mohamed 7,  Ningping Feng 11,  Jithesh Jose Augustine 12,  Alessandro Sgambato 8 13,  Giampaolo Tortora 8 9,  Giulio F Draetta 7,  Giovanni Tonon 5,  Andrew Futreal 7,  Virginia Giuliani 11,  Alessandro Carugo 14,  Andrea Viale 7,  Michael P Kim 12,  Timothy P Heffernan 11,  Linghua Wang 7 15,  Raghu Kalluri 6 16 17,  Davide Cittaro 18,  Fei Chen 19 20,  Giannicola Genovese 21 22 23 24
Affiliations

Affiliations

  • 1 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. LPerelli@mdanderson.org.
  • 2 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 4 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
  • 5 Center for Omics Sciences, IRCCS San Raffaele Institute, Milan, Italy.
  • 6 Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.
  • 9 Medical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
  • 10 Nerviano Medical Sciences, NMS Group, Milan, Italy.
  • 11 TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 12 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 13 Multiplex Spatial Imaging Facility, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
  • 14 Department of Biology, IRBM, Rome, Italy.
  • 15 The University of Texas MD Anderson Cancer Center, UT Health Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX, USA.
  • 16 Department of Bioengineering, Rice University, Houston, TX, USA.
  • 17 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 18 Center for Omics Sciences, IRCCS San Raffaele Institute, Milan, Italy. cittaro.davide@hsr.it.
  • 19 Broad Institute of Harvard and MIT, Cambridge, MA, USA. chenf@broadinstitute.org.
  • 20 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. chenf@broadinstitute.org.
  • 21 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. GGenovese@mdanderson.org.
  • 22 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. GGenovese@mdanderson.org.
  • 23 TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. GGenovese@mdanderson.org.
  • 24 David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. GGenovese@mdanderson.org.
  • # Contributed equally.
PMID: 40044861 DOI: 10.1038/s41586-025-08671-2
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.

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