Abstract
Cells induced into senescence exhibit a marked increase in the secretion of pro-inflammatory cytokines termed senescence-associated secretory phenotype (SASP). Here we report that SASP from senescent stromal fibroblasts promote spontaneous morphological changes accompanied by an aggressive migratory behavior in originally non-motile human breast cancer cells. This phenotypic switch is coordinated, in space and time, by a dramatic reorganization of the actin and microtubule filament networks, a discrete polarization of EB1 comets, and an unconventional front-to-back inversion of nucleus-MTOC polarity. SASP-induced morphological/migratory changes are critically dependent on microtubule integrity and dynamics, and are coordinated by the inhibition of RhoA and cell contractility. RhoA/ROCK inhibition reduces focal adhesions and traction forces, while promoting a novel gliding mode of migration.
Keywords:
SASP; senescence.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Actins / metabolism
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Breast Neoplasms / enzymology*
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Cell Movement* / drug effects
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Cell Polarity
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Cell Shape
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Cellular Senescence*
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Female
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Fibroblasts / metabolism*
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Focal Adhesions / enzymology
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Humans
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MCF-7 Cells
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Microtubules / enzymology
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Mutation
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Myosins / metabolism*
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Paracrine Communication*
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Phenotype
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Protein Kinase Inhibitors / pharmacology
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Signal Transduction
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Time Factors
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Transfection
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rho-Associated Kinases / antagonists & inhibitors
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rho-Associated Kinases / metabolism*
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rhoA GTP-Binding Protein / antagonists & inhibitors
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism*
Substances
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Actins
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Microtubule-Associated Proteins
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Protein Kinase Inhibitors
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RHOA protein, human
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rho-Associated Kinases
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Myosins
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rhoA GTP-Binding Protein