title: Genomic Instability Is Induced by Persistent Proliferation of Cells Undergoing Epithelial-to-Mesenchymal Transition.
abstract: TGF-β secreted by tumor stroma induces epithelial-to-mesenchymal transition (EMT) in cancer cells, a reversible phenotype linked to cancer progression and drug resistance. However, exposure to stromal signals may also lead to heritable changes in cancer cells, which are poorly understood. We show that epithelial cells failing to undergo proliferation arrest during TGF-β-induced EMT sustain mitotic abnormalities due to failed cytokinesis, resulting in aneuploidy. This genomic instability is associated with the suppression of multiple nuclear envelope proteins implicated in mitotic regulation and is phenocopied by modulating the expression of LaminB1. While TGF-β-induced mitotic defects in proliferating cells are reversible upon its withdrawal, the acquired genomic abnormalities persist, leading to increased tumorigenic phenotypes. In metastatic breast cancer patients, increased mesenchymal marker expression within single circulating tumor cells is correlated with genomic instability. These observations identify a mechanism whereby microenvironment-derived signals trigger heritable genetic changes within cancer cells, contributing to tumor evolution.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Valentine
authors.initials: V
authors.lastname: Comaills
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kabeche
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Morris
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Rémi
authors.initials: R
authors.lastname: Buisson
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Marissa Wells
authors.initials: MW
authors.lastname: Madden
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: LiCausi
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Boukhali
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Pan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Aceto
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Srinjoy
authors.initials: S
authors.lastname: Sil
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Tilak
authors.initials: T
authors.lastname: Sundaresan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yae
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Nicole Vincent
authors.initials: NV
authors.lastname: Jordan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Miyamoto
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haas
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: maheswaran@helix.mgh.harvard.edu.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D034921:Lamin Type B / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D034921:Lamin Type B; D053773:Transforming Growth Factor beta1