title: Nuclear envelope rupture and repair during cancer cell migration.
abstract: During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we investigated mammalian tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increased with cell confinement and with depletion of nuclear lamins, NE proteins that structurally support the nucleus. Cells restored NE integrity using components of the endosomal sorting complexes required for transport III (ESCRT III) machinery. Our findings indicate that cell migration incurs substantial physical stress on the NE and its content and requires efficient NE and DNA damage repair for cell survival.
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
authors.forename: Celine M
authors.initials: CM
authors.lastname: Denais
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Gilbert
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Isermann
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: McGregor
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Mariska
authors.initials: M
authors.lastname: te Lindert
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Bettina
authors.initials: B
authors.lastname: Weigelin
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Davidson
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, Nijmegen, Netherlands. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Cancer Genomics Center, Netherlands (CGC.nl).
authors.forename: Peter
authors.initials: P
authors.lastname: Friedl
authors.affiliation: Department of Cell Biology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Katarina
authors.initials: K
authors.lastname: Wolf
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA. jan.lammerding@cornell.edu.
authors.forename: Jan
authors.initials: J
authors.lastname: Lammerding
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D002843:Chromatin / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006801:Humans; D034882:Lamins / Q000172:deficiency; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009685:Nuclear Envelope / Q000378:metabolism / Q000473:pathology*; D013314:Stress, Mechanical; D059016:Tumor Microenvironment
chemical_list: D002843:Chromatin; D056827:Endosomal Sorting Complexes Required for Transport; D034882:Lamins