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Dev Cell. 2018 Nov 19;47(4):409-424.e9. doi: 10.1016/j.devcel.2018.10.026.

Oxidative Stress in Cells with Extra Centrosomes Drives Non-Cell-Autonomous Invasion.

Author information

1
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
2
Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.
3
Integrative Cell Signalling and Proteomics, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
4
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: s.godinho@qmul.ac.uk.

Abstract

Centrosomal abnormalities, in particular centrosome amplification, are recurrent features of human tumors. Enforced centrosome amplification in vivo plays a role in tumor initiation and progression. However, centrosome amplification occurs only in a subset of cancer cells, and thus, partly due to this heterogeneity, the contribution of centrosome amplification to tumors is unknown. Here, we show that supernumerary centrosomes induce a paracrine-signaling axis via the secretion of proteins, including interleukin-8 (IL-8), which leads to non-cell-autonomous invasion in 3D mammary organoids and zebrafish models. This extra centrosomes-associated secretory phenotype (ECASP) promotes invasion of human mammary cells via HER2 signaling activation. Further, we demonstrate that centrosome amplification induces an early oxidative stress response via increased NOX-generated reactive oxygen species (ROS), which in turn mediates secretion of pro-invasive factors. The discovery that cells with extra centrosomes can manipulate the surrounding cells highlights unexpected and far-reaching consequences of these abnormalities in cancer.

KEYWORDS:

HER2; IL-8; ROS; cancer; centrosome amplification; invasion; paracrine signaling; secretion; senescence

PMID:
30458137
PMCID:
PMC6251975
DOI:
10.1016/j.devcel.2018.10.026
[Indexed for MEDLINE]
Free PMC Article

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