Senescent stromal cells induce cancer cell migration via inhibition of RhoA/ROCK/myosin-based cell contractility.
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.
Johns Hopkins Physical Sciences - Oncology Center, The Johns Hopkins University, Baltimore, Maryland, USA.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, USA.
Ivie
I
Aifuwa
Johns Hopkins Physical Sciences - Oncology Center, The Johns Hopkins University, Baltimore, Maryland, USA.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, USA.
Anjil
A
Giri
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, USA.
Nick
N
Longe
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, USA.
Sang Hyuk
SH
Lee
Johns Hopkins Physical Sciences - Oncology Center, The Johns Hopkins University, Baltimore, Maryland, USA.|Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Steven S
SS
An
Johns Hopkins Physical Sciences - Oncology Center, The Johns Hopkins University, Baltimore, Maryland, USA.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, USA.|Departments of Pathology and Oncology, Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Denis
D
Wirtz
D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity; D048430:Cell Shape; D016922:Cellular Senescence; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D022001:Focal Adhesions / Q000201:enzymology; D006801:Humans; D061986:MCF-7 Cells; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000201:enzymology; D009154:Mutation; D009218:Myosins / Q000378:metabolism*; D019899:Paracrine Communication; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; C066737:RHOA protein, human; D054460:rho-Associated Kinases; D009218:Myosins; D020742:rhoA GTP-Binding Protein
SASP; senescence